Estrogen receptor modulators

ABSTRACT

The present invention relates to compounds and derivatives thereof, their cynthesis, and their use as estrogen receptor modulators. The compound of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, cartilage degeneration, endometriosis, uterine fibroid desease, hot flashes, increased levels of LDL cholestterol, cardiovascular disease, impairment of cognitive functioning, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muschle cell proliferation, obesity, incontinence, and cancer, in particular of the breast, uterus and prostate.

BACKGROUND OF THE INVENTION

Naturally occurring and synthetic estrogens have broad therapeuticutility, including: relief of menopausal symptoms, treatment of acne,treatment of dysmenorrhea and dysfunctional uterine bleeding, treatmentof osteoporosis, treatment of hirsutism, treatment of prostatic cancer,treatment of hot flashes and prevention of cardiovascular disease.Because estrogen is very therapeutically valuable, there has been greatinterest in discovering compounds that mimic estrogen-like behavior inestrogen responsive tissues.

For example, estrogen-like compounds would be beneficial in thetreatment and prevention of bone loss. Bone loss occurs in a wide rangeof subjects, including women that are post-menopausal or have had ahysterectomy, patients who were or are currently being treated withcorticosteroids, and patients having gonadal dysgenesis. The currentmajor bone diseases of public concern are osteoporosis, hypercalcemia ofmalignancy, osteopenia due to bone metastases, periodontal disease,hyperparathyroidism, periarticular erosions in rheumatoid arthritis,Paget's disease, immobilization-induced osteopenia, andglucocorticoid-induced osteoporosis. All of these conditions arecharacterized by bone loss, resulting from an imbalance between boneresorption, i.e. breakdown, and bone formation, which continuesthroughout life at the rate of about 14% per year on the average.However, the rate of bone turnover differs from site to site, forexample, it is higher in the trabecular bone of the vertebrae and thealveolar bone in the jaws than in the cortices of the long bones. Thepotential for bone loss is directly related to turnover and can amountto over 5% per year in vertebrae immediately following menopause, acondition which leads to increased fracture risk.

In the U.S., there are currently about 20 million people with detectablefractures of the vertebrae due to osteoporosis. In addition, there areabout 250,000 hip fractures per year attributed to osteoporosis. Thisclinical situation is associated with a 12% mortality rate within thefirst two years, while 30% of the patients require nursing home careafter the fracture.

Osteoporosis affects approximately 20 to 25 million post-menopausalwomen in the U.S. alone. It has been theorized that the rapid loss ofbone mass in these women is due to the cessation of estrogen productionof the ovaries. Since studies have shown that estrogen slows thereduction of bone mass due to osteoporosis, estrogen replacement therapyis a recognized treatment for post-menopausal osteoporosis.

In addition to bone mass, estrogen appears to have an effect on thebiosynthesis of cholesterol and cardiovascular health. Statistically,the rate of occurrence of cardiovascular disease is roughly equal inpostmenopausal women and men; however, premenopausal women have a muchlower incidence of cardiovascular disease than men. Becausepostmenopausal women are estrogen deficient, it is believed thatestrogen plays a beneficial role in preventing cardiovascular disease.The mechanism is not well understood, but evidence indicates thatestrogen can upregulate the low density lipid (LDL) cholesterolreceptors in the liver to remove excess cholesterol.

Postmenopausal women given estrogen replacement therapy experience areturn of lipid levels to concentrations comparable to levels associatedwith the premenopausal state. Thus, estrogen replacement therapy couldbe an effective treatment for such disease. However, the side effectsassociated with long term estrogen use limit the use of thisalternative.

Other disease states that affect postmenopausal women includeestrogen-dependent breast cancer and uterine cancer. Anti-estrogencompounds, such as tamoxifen, have commonly been used as chemotherapy totreat breast cancer patients. Tamoxifen, a dual antagonist and agonistof estrogen receptors, is beneficial in treating estrogen-dependentbreast cancer. However, treatment with tamoxifen is less than idealbecause tamoxifen's agonist behavior enhances its unwanted estrogenicside effects. For example, tamoxifen and other compounds that agonizeestrogen receptors tend to increase cancer cell production in theuterus. A better therapy for such cancers would be an anti-estrogencompound that has negligible or nonexistent agonist properties.

Although estrogen can be beneficial for treating pathologies such asbone loss, increased lipid levels, and cancer, long-term estrogentherapy has been implicated in a variety of disorders, including anincrease in the risk of uterine and endometrial cancers. These and otherside effects of estrogen replacement therapy are not acceptable to manywomen, thus limiting its use.

Alternative regimens, such as a combined progestogen and estrogen dose,have been suggested in an attempt to lessen the risk of cancer. However,such regimens cause the patient to experience withdrawal bleeding, whichis unacceptable to many older women. Furthermore, combining estrogenwith progestogen reduces the beneficial cholesterol-lowering effect ofestrogen therapy. In addition, the long term effects of progestogentreatment are unknown.

In addition to post-menopausal women, men suffering from prostaticcancer can also benefit from anti-estrogen compounds. Prostatic canceris often endocrine-sensitive; androgen stimulation fosters tumor growth,while androgen suppression retards tumor growth. The administration ofestrogen is helpful in the treatment and control of prostatic cancerbecause estrogen administration lowers the level of gonadotropin and,consequently, androgen levels.

The estrogen receptor has been found to have two forms: ERα and ERβ.Ligands bind differently to these two forms, and each form has adifferent tissue specificity to binding ligands. Thus, it is possible tohave compounds that are selective for ERα or ERβ, and therefore confer adegree of tissue specificity to a particular ligand.

What is needed in the art are compounds that can produce the samepositive responses as estrogen replacement therapy without the negativeside effects. Also needed are estrogen-like compounds that exertselective effects on different tissues of the body. Specifically, whatis needed are compounds that exhibit a potent, selective affinity forERα, and act as antagonists on breast and uterine tissues and asagonists on bone and lipids.

The compounds of the instant invention are ligands for estrogenreceptors and as such may be useful for treatment or prevention of avariety of conditions related to estrogen functioning including: boneloss, bone fractures, osteoporosis, glucocorticoid induced osteoporosis,Paget's disease, abnormally increased bone turnover, periodontaldisease, tooth loss, rheumatoid arthritis, osteoarthritis,periprosthetic osteolysis, osteogenesis imperfecta, metastatic bonedisease, hypercalcemia of malignancy, and multiple myeloma, cartilagedegeneration, endometriosis, uterine fibroid disease, cancer of thebreast, uterus or prostate, hot flashes, cardiovascular disease,impairment of cognitive function, cerebral degenerative disorders,restenosis, gynecomastia, vascular smooth muscle cell proliferation,obesity and incontinence.

SUMMARY OF THE INVENTION

The present invention relates to compounds that are capable of treatingand/or preventing a variety of conditions related to estrogenfunctioning. One embodiment of the present invention is illustrated by acompound of Formula I, and the pharmaceutically acceptable salts,stereoisomers, and chiral forms thereof:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds useful as estrogen receptormodulators. Compounds of the present invention are described by thefollowing chemical formula:

wherein R¹ is selected from the group consisting of hydrogen or halo;

-   R² is selected from hydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃;-   R³ is selected from hydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃;-   R⁴ is selected from C₁₋₃ alkyl, CH₂F, CHF₂, CF₃ or hydrogen with the    proviso that R4 and R7are not simultaneously hydrogen;-   R⁵ is selected from hydrogen or hydroxyl;-   R⁶ is selected from hydrogen or hydroxyl;-   R⁷ is selected from C₁₋₃ alkyl, CH₂F or hydrogen with the proviso    that R⁴ and R7 are not simultaneously hydrogen;-   R⁸ is selected from hydrogen, C₁₋₃ alkyl or CH₂F;    or a pharmaceutically acceptable salt, stereoisomer, or chiral form    thereof.

In one class of compounds of the present invention, R⁴ is CH₃, or apharmaceutically acceptable salt, stereoisomer, or chiral form thereof.

A class of compounds of the present invention is described by thechemical formula:

wherein R¹ is selected from hydrogen or halo;

-   R² is selected from hydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃;-   R³ is selected from hydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃;-   R⁵ is selected from hydrogen or hydroxyl;-   R⁶ is selected from hydrogen or hydroxyl;-   R⁷ is selected from hydrogen, C₁₋₃ alkyl or CH₂F;-   R⁸ is selected from hydrogen, C₁₋₃ alkyl or CH₂F;    or a pharmaceutically acceptable salt, stereoisomer, or chiral form    thereof.

In one class of compounds of the present invention, R¹ is selected fromthe group consisting of hydrogen and fluoro.

Non-limiting examples of the present invention include:

-   (2S,3R)-3-(4-hydroxyphenyl)-2-(4-{[(2S)-2-pyrrolidin-1-ylpropyl]oxy}phenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-3-(3-hydroxyphenyl)-2-(4-{[(2S)-2-pyrrolidin-1-ylpropyl]oxy}phenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-2-[4-({(2S)-2-[(3S,4S)-3,4-dimethylpyrrolidin-1-yl]propyl}oxy)phenyl]-5-fluoro-3-(3-hydroxyphenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-5-fluoro-3-(3-hydroxyphenyl)-2-(4-{[(2S)-2-pyrrolidin-1-ylpropyl]oxy}phenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-3-(4-hydroxyphenyl)-2-[4-({(2S)-2-[(3R)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-2-[4-({(2S)-2-[(3R,4R)-3,4-dimethylpyrrolidin-1-yl]propyl}oxy)phenyl]-3-(4-hydroxyphenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-2-[4-({(2S)-2-[(3S,4S)-3,4dimethylpyrrolidin-1-yl]propyl}oxy)phenyl]-3-(4-hydroxyphenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-2-[4-({(2S)-2-[(3R,4S)-3,4dimethylpyrrolidin-1-yl]propyl}oxy)phenyl]-3-(4-hydroxyphenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-5-fluoro-3-(3-hydroxyphenyl)-2-[4-({(2S)-2-[(3R)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-5-fluoro-3-(4-hydroxyphenyl)-2-[4-({(2S)-2-[(3R)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathlin-6-ol;-   (2S,3R)-2-[4-({(2S)-2-[(3R,4R)-3,4-dimethylpyrrolidin-1-yl]propyl}oxy)phenyl]-3-(3-hydroxyphenyl)-2,3-dihydro-1,4benzoxathiin-6-ol;-   (2S,3R)-2-[4-({(2S)-2-[(3R,4S)-3,4-dimethylpyrrolidin-1-yl]propyl}oxy)phenyl]-5-fluoro-3-(3-hydroxyphenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-3-(3-hydroxyphenyl)-2-[4-({(2S)-2-[(3R)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-3-(4-hydroxyphenyl)-2-[4-({(2S)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-3-(3-hydroxyphenyl)-2-[4-({(2S)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-5-fluoro-3-(4-hydroxyphenyl)-2-[4-({(2R)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl-}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-5-fluoro-3-(3-hydroxyphenyl)-2-[4-({(2R)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-3-(4-hydroxyphenyl)-2-[4-({(2R)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;-   (2S,3R)-3-(3-hydroxyphenyl)-2-[4({(2R)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4benzoxathiin-6-ol;    and the pharmaceutically acceptable salts, stereoisomers and chiral    forms thereof.

A class of compounds of the present invention is described by thechemical formula:

wherein R¹ is selected from hydrogen or halo;

-   R² is selected from hydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃;-   R³ is selected from hydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃;-   R⁵ is selected from hydrogen or hydroxyl;-   R⁶ is selected from hydrogen or hydroxyl;-   R⁷ is selected from hydrogen, C₁₋₃ alkyl or CH₂F;-   R⁸ is selected from hydrogen, C₁₋₃ alkyl or CH₂F;    or a pharmaceutically acceptable salt, stereoisomer, or chiral form    thereof.

Also included within the scope of the present invention is apharmaceutical composition which is comprised of a compound of Formula Ias described above and a pharmaceutically acceptable carrier. Theinvention is also contemplated to encompass a pharmaceutical compositionwhich is comprised of a pharmaceutically acceptable carrier and any ofthe compounds specifically disclosed in the present application. Thepresent invention also relates to methods for making the pharmaceuticalcompositions of the present invention. The present invention is alsorelated to processes and intermediates useful for making the compoundsand pharmaceutical compositions of the present invention. These andother aspects of the invention will be apparent from the teachingscontained herein.

Utilities

The compounds of the present invention are selective modulators ofestrogen receptors and are therefore useful to treat or prevent avariety of diseases and conditions related to estrogen receptorfunctioning in mammals, preferably humans. Specifically, the compoundsof the present invention exhibit a potent, selective affinity for ERαThey also act as antagonists on breast and uterine tissue and asagonists on bone and lipids. The compounds of the present inventionimpart a substantially greater antagonism of estradiol, while exhibitingsubstantially less agonism on uterine tissue, without loss of receptoraffinity or selectivity, as compared to previously known compounds.

“A variety of diseases and conditions related to estrogen receptorfunctioning” includes, but is not limited to, bone loss, bone fractures,osteoporosis, glucocorticoid induced osteoporosis, Paget's disease,abnormally increased bone turnover, periodontal disease, tooth loss,rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis,osteogenesis imperfecta, metastatic bone disease, hypercalcemia ofmalignancy, and multiple myeloma, cartilage degeneration, endometriosis,uterine fibroid disease, cancer of the breast, uterus or prostate, hotflashes, cardiovascular disease, impairment of cognitive function,cerebral degenerative disorders, restenosis, gynecomastia, vascularsmooth muscle cell proliferation, obesity and incontinence. In treatingsuch conditions with the instantly claimed compounds, the requiredtherapeutic amount will vary according to the specific disease and isreadily ascertainable by those skilled in the art. Although bothtreatment and prevention are contemplated by the scope of the invention,the treatment of these conditions is the preferred use.

The present invention also relates to methods for eliciting an estrogenreceptor modulating effect in a mammal in need thereof by administeringthe compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an estrogenreceptor antagonizing effect in a mammal in need thereof byadministering the compounds and pharmaceutical compositions of thepresent invention. The estrogen receptor antagonizing effect can beeither an ERα antagonizing effect, an ERβ antagonizing effect or a mixedERα and ERβ antagonizing effect.

The present invention also relates to methods for eliciting an estrogenreceptor agonizing effect in a mammal in need thereof by administeringthe compounds and pharmaceutical compositions of the present invention.The estrogen receptor agonizing effect can be either an ERα agonizingeffect, an ERβ agonizing effect or a mixed ERα and ERβ agonizing effect.

The present invention also relates to methods for treating or preventingdisorders related to estrogen functioning, bone loss, bone fractures,osteoporosis, glucocorticoid induced osteoporosis, Paget's disease,abnormally increased bone turnover, periodontal disease, tooth loss,rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis,osteogenesis imperfecta, metastatic bone disease, hypercalcemia ofmalignancy, and multiple myeloma, cartilage degeneration, endometriosis,uterine fibroid disease, cancer of the breast, uterus or prostate, hotflashes, cardiovascular disease, impairment of cognitive function,cerebral degenerative disorders, restenosis, gynecomastia, vascularsmooth muscle cell proliferation, obesity and incontinence in a mammalin need thereof by administering the compounds and pharmaceuticalcompositions of the present invention. Exemplifying the invention is amethod of treating or preventing osteoporosis. Exemplifying theinvention is a method of treating or preventing bone loss. Exemplifyingthe invention is a method of treating or preventing metastatic bonedisease. Exemplifying the invention is a method of treating orpreventing cancer. Exemplifying the invention is a method of treating orpreventing cardiovascular disease.

An embodiment of the invention is a method for treating or preventingcancer, especially of the breast, uterus or prostate, in a mammal inneed thereof by administering the compounds and pharmaceuticalcompositions of the present invention. The utility of SERMs for thetreatment of breast, uterine or prostate cancer is known in theliterature, see T. J. Powles, “Breast cancer prevention,” Oncologist2002; 7(1):60-4; Park, W. C. and Jordan, V. C., “Selective estrogenreceptor modulators (SERMS) and their roles in breast cancerprevention.” Trends Mol Med. 2002 February; 8(2):82-8; Wolff, A. C. etal., “Use of SERMs for the adjuvant therapy of early-stage breastcancer,” Ann N Y Acad Sci. 2001 December; 949:80-8; Steiner, M. S. etal., “Selective estrogen receptor modulators for the chemoprevention ofprostate cancer,” Urology 2001 April; 57(4 Suppl 1):68-72.

Another embodiment of the invention is a method of treating orpreventing metastatic bone disease in a mammal in need thereof byadministering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above. Theutility of SERMs in the treatment of metastatic bone disease is known inthe literature, see, Campisi, C. et al., “Complete resoultion of breastcancer bone metastasis through the use of beta-interferon andtamoxifen,” Eur J Gynaecol Oncol 1993;14(6):479-83.

Another embodiment of the invention is a method of treating orpreventing gynecomastia in a mammal in need thereof by administering tothe mammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The utility of SERMs in thetreatment of gynecomastia is known in the literature, see, Ribeiro, G.and Swindell R., “Adjuvant tamoxifen for male breast cancer.” Br JCancer 1992; 65:252-254; Donegan, W., “Cancer of the Male Breast,” JGSMVol. 3, Issue 4, 2000.

Another embodiment of the invention is a method of treating orpreventing post-menopausal osteoporosis, glucocorticoid osteoporosis,hypercalcemia of malignancy, bone loss and bone fractures in a mammal inneed thereof by administering to the mammal a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove. The utility of SERMs to treat or prevent osteoporosis,hypercalcemia of malignancy, bone loss or bone fractures is known in theliterature, see Jordan, V. C. et al., “Selective estrogen receptormodulation and reduction in risk of breast cancer, osteoporosis andcoronary heart disease,” Natl Cancer Inst 2001 October; 93(19):1449-57;Bjarnason, N H et al., “Six and twelve month changes in bone turnoverare realted to reduction in vertebral fracture risk during 3 years ofraloxifene treatment in postemenopausal osteoporosis,” Osteoporosis Int2001; 12(11):922-3; Fentiman I. S., “Tamoxifen protects againststeroid-induced bone loss,” Eur J Cancer 28:684685 (1992); Rodan, G. A.et al., “Therapeutic Approaches to Bone Diseases,” Science Vol 289, 1Sep. 2000.

Another embodiment of the invention is a method of treating ofpreventing periodontal disease or tooth loss in a mammal in need thereofby administering to the mammal a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described above. The useof SERMs to treat periodontal disease or tooth loss in a mammal is knownin the literature, see Rodan, G. A. et al., “Terapeutic Approaches toBone Diseases,” Science Vol 289, 1 Sep. 2000 pp. 1508-14.

Another embodiment of the invention is a method of treating ofpreventing Paget's disease in a mammal in need thereof by administeringto the mammal a therapeutically effective amount of any of the compoundsor pharmaceutical compositions described above. The use of SERMs totreat Paget's disease in a mammal is known in the literature, see Rodan,G. A. et al., “Therapeutic Approaches to Bone Diseases,” Science Vol289, 1 September 2000 pp. 1508-14.

Another embodiment of the invention is a method of treating orpreventing uterine fibroid disease in a mammal in need thereof byadministering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above. The use ofSERMs to treat uterine fibroids, or uterine leiomyomas, is known in theliterature, see Palomba, S., et al, “Effects of raloxifene treatment onuterine leiomyomas in postmenopausal women,” Fertil Steril. 2001 July;76(1):38-43.

Another embodiment of the invention is a method of treating orpreventing obesity in a mammal in need thereof by administering to themammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The use of SERMs to treatobesity is known in the literature, see Picard, F. et al., “Effects ofthe estrogen antagonist EM-652.HCl on energy balance and lipidmetabolism in ovariectomized rats,” Int J Obes Relat Metab Disord. 2000July; 24(7):830-40.

Another embodiment of the invention is a method of treating orpreventing cartilage degeneration, rheumatoid arthritis orosteoarthritis in a mammal in need thereof by administering to themammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The use of SERMs to treatcartilage degeneration, rheumatoid arthritis or osteoarhritis is knownin the literature, see Badger, A. M. et al., “Idoxifene, a novelselective estrogen receptor modulator, is effective in a rat model ofadjuvant-induced arthritis.” J Pharmacol Exp Ther. 1999 Dec;291(3):1380-6.

Another embodiment of the invention is a method of treating orpreventing endometriosis in a mammal in need thereof by administering tothe mammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The use of SERMs to treatendometriosis is known in the art, see Steven R. Goldstein, “The Effectof SERMs on the Endometrium,” Annals of the New York Academy of Sciences949:237-242 (2001).

Another embodiment of the invention is a method of treating orpreventing urinary incontinence in a mammal in need thereof byadministering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above. The use ofSERMs to treat urinary incontinence is known in the art, see, Goldstein,S. R., “Raloxifene effect on frequency of surgery for pelvic floorrelaxation,” Obstet Gynecol. 2001 July; 98(1):91-6 and Matsubara, S., etal., “Estrogen Levels Influence Beta-3-adrenoreceptor-mediatedRelaxation of the Female Rat Detrusor Muscle,” Urology 59: 621-625,2002.

Another embodiment of the invention is a method of treating orpreventing cardiovascular disease, restenosis, lowering levels of LDLcholesterol and inhibiting vascular smooth muscle cell proliferation ina mammal in need thereof by administering to the mammal atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The utility of SERMs intreating or preventing cardiovascular disease, restenosis, loweringlevels of LDL cholesterol and inhibiting vascular smooth muscle cellproliferation is known in the art, see Nuttall, M E et al., “Idoxifene:a novel selective estrogen receptor modulator prevents bone loss andlowers cholesterol levels in ovariectomized rats and decreases uterineweight in intact rats,” Endocrinology 1998 December; 139(12):522434;Jordan, V. C. et al., “Selective estrogen receptor modulation andreduction in risk of breast cancer, osteoporosis and coronary heartdisease,” Natl Cancer Inst 2001 October; 93(19):1449-57; Guzzo J A.,“Selective estrogen receptor modulators—a new age of estrogens incardiovascular disease?,” Clin Cardiol 2000 January; 23(1):15-7;Simoncini T, Genazzani A R., “Direct vascular effects of estrogens andselective estrogen receptor modulators,” Curr Opin Obstet Gynecol 2000June; 12(3):181-7.

Another embodiment of the invention is a method of treating orpreventing the impairment of cognitive functioning or cerebraldegenerative disorders in a mammal in need thereof by administering tothe mammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The utility of SERMs toprevent the impairment of cognitive functioning is known in the art, seeYaffe, K., K. Krueger, S. Sarkar, et al. 2001, “Cognitive function inpostmenopausal women treated with raloxifene,” N. Eng. J. Med. 344:1207-1213.

Exemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of osteoporosis in a mammal in need thereof. Still furtherexemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment and/orprevention of: bone loss, bone resorption, bone fractures, metastaticbone disease and/or disorders related to estrogen functioning.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

In the case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch, and lubricating agents, such asmagnesium stearate, are commonly added. For oral administration incapsule form, useful diluents include lactose and dried corn starch. Fororal use of a therapeutic compound according to this invention, theselected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. For oraladministration in the form of a tablet or capsule, the active drugcomponent can be combined with an oral, non-toxic, pharmaceuticallyacceptable, inert carrier such as lactose, starch, sucrose, glucose,methyl cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate, mannitol, sorbitol and the like; for oral administration inliquid form, the oral drug components can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like. When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening and/or flavoring agents may be added. Forintramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

The compounds of the present invention can also be admninistered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polyactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

The instant compounds are also useful in combination with known agentsuseful for treating or preventing bone loss, bone fractures,osteoporosis, glucocorticoid induced osteoporosis, Paget's disease,abnormally increased bone turnover, periodontal disease, tooth loss,rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis,osteogenesis imperfecta, metastatic bone disease, hypercalcemia ofmalignancy, and multiple myeloma, cartilage degeneration, endometriosis,uterine fibroid disease, cancer of the breast, uterus or prostate, hotflashes, cardiovascular disease, impairment of cognitive function,cerebral degenerative disorders, restenosis, gynecomastia, vascularsmooth muscle cell proliferation, obesity and incontinence. Combinationsof the presently disclosed compounds with other agents useful intreating or preventing osteoporosis or other bone disorders are withinthe scope of the invention. A person of ordinary skill in the art wouldbe able to discern which combinations of agents would be useful based onthe particular characteristics of the drugs and the disease involved.Such agents include the following: an organic bisphosphonate; acathepsin K inhibitor; an estrogen or an estrogen receptor modulator; anandrogen receptor modulator; an inhibitor of osteoclast proton ATPase;an inhibitor of HMG-CoA reductase; an inhibitor of cholesxterol estertransfer protein; an integrin receptor antagonist; an osteoblastanabolic agent, such as PmH; calcitonin; Vitamin D or a syntheticVitamin D analogue; an aromatase inhibitor; selective serotonin reuptakeinhibitors (SSRIs); and the pharmaceutically acceptable salts andmixtures thereof. A preferred combination is a compound of the presentinvention and an organic bisphosphonate. Another preferred combinationis a compound of the present invention and a cathepsin K inhibitor.Another preferred combination is a compound of the present invention andan estrogen. Another preferred combination is a compound of the presentinvention and an androgen receptor modulator. Another preferredcombination is a compound of the present invention and an osteoblastanabolic agent.

“Organic bisphosphonate” includes, but is not limited to, compounds ofthe chemical formula

wherein n is an integer from 0 to 7 and wherein A and X areindependently selected from the group consisting of H, OH, halogen,NH₂,SH, phenyl, C1-C30 alkyl, C3-C30 branched or cycloalkyl, bicyclicring structure containing two or three N, C1-C30 substituted alkyl,C1-C10 alkyl substituted NH₂, C3-C10 branched or cycloalkyl substitutedNH₂, C1-C10 dialilyl substituted NH₂, C1-C10 alkoxy, C1-C10 alkylsubstituted thio, thiophenyl, halophenylthio, C1-C10 alkyl substitutedphenyl, pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl,and benzyl, such that both A and X are not selected from H or OH when nis 0; or A and X are taken together with the carbon atom or atoms towhich they are attached to form a C3-C10 ring.

In the foregoing chemical formula, the alkyl groups can be straight,branched, or cyclic, provided sufficient atoms are selected for thechemical formula. The C1-C30 substituted alkyl can include a widevariety of substituents, nonlimiting examples which include thoseselected from the group consisting of phenyl, pyridyl, furanyl,pyrrolidinyl, imidazonyl, NH₂, C1-C10 alkyl or dialkyl substitutedNH₂,OH, SH, and C1-C10 alkoxy.

The foregoing chemical formula is also intended to encompass complexcarbocyclic, aromatic and hetero atom structures for the A and/or Xsubstituents, nonlimiting examples of which include naphthyl, quinolyl,isoquinolyl, adamantyl, and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives of the bisphosphonatesare also useful herein. Non-limiting examples of salts include thoseselected from the group consisting alkali metal, alkaline metal,ammonium, and mono-, di-, tri-, or tetra-C1-C30-alkyl-substitutedammonium. Preferred salts are those selected from the group consistingof sodium, potassium, calcium, magnesium, and ammonium salts. Morepreferred are sodium salts. Non-limiting examples of derivatives includethose selected from the group consisting of esters, hydrates, andamides.

It should be noted that the terms “bisphosphonate” and“bisphosphonates”, as used herein in referring to the therapeutic agentsof the present invention are meant to also encompass diphosphonates,biphosphonic acids, and diphosphonic acids, as well as salts andderivatives of these materials. The use of a specific nomenclature inreferring to the bisphosphonate or bisphosphonates is not meant to limitthe scope of the present invention, unless specifically indicated.Because of the mixed nomenclature currently in use by those of ordinaryskill in the art, reference to a specific weight or percentage of abisphosphonate compound in the present invention is on an acid activeweight basis, unless indicated otherwise herein. For example, the phrase“about 5 mg of a bone resorption inhibiting bisphosphonate selected fromthe group consisting of alendronate, pharmaceutically acceptable saltsthereof, and mixtures thereof, on an alendronic acid active weightbasis” means that the amount of the bisphosphonate compound selected iscalculated based on 5 mg of alendronic acid.

Non-limiting examples of bisphosphonates useful herein include thefollowing:

Alendronic acid, 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid.

Alendronate (also known as alendronate sodium or alendronate monosodiumtrihydrate), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acidmonosodium trihydrate.

Alendronic acid and alendronate are described in U.S. Pat. No.4,922,007, to Kieczykowski et al., issued May 1, 1990; U.S. Pat. No.5,019,651, to Kieczykowski et al., issued May 28, 1991; U.S. Pat. No.5,510,517, to Dauer et al., issued Apr. 23, 1996; U.S. Pat. No.5,648,491, to Dauer et al., issued Jul. 15, 1997, all of which areincorporated by reference herein in their entirety.

Cycloheptylaminomethylene-1,1-bisphosphonic acid, YM 175, Yaamanouchi(incadronate, formerly known as cimadronate), as described in U.S. Pat.No. 4,970,335, to Isomura et al., issued Nov. 13, 1990, which isincorporated by reference herein in its entirety.

1,1-dichloromethylene-1,1-diphosphonic acid (clodronic acid), and thedisodium salt (clodronate, Procter and Gamble), are described in BelgiumPatent 672,205 (1966) and J. Org. Chem 32, 4111 (1967), both of whichare incorporated by reference herein in their entirety.

1-hydroxy-3-(1-pyrrolidinyl)-propylidene-1,1-bisphosphonic acid(EB-1053).

1-hydroxyethane-1,1-diphosphonic acid (etidronic acid).

1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid,also known as BM-210955, Boehringer-Mannheim (ibandronate), is describedin U.S. Pat. No. 4,927,814, issued May 22, 1990, which is incorporatedby reference herein in its entirety.

1-hydroxy-2-imidazo-(1,2-a)pyridin-3-yethylidene (minodronate).

6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid (neridronate).

3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid(olpadronate).

3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid (pamidronate).

[2-(2-pyridinyl)ethylidene]-1,1-bisphosphonic acid (piridronate) isdescribed in U.S. Pat. No. 4,761,406, which is incorporated by referencein its entirety.

1-hydroxy-2-(3-pyridinyl)-ethylidene-1,1-bisphosphonic acid(risedronate).

4-chlorophenyl)thiomethane-1,1-disphosphonic acid (tiludronate) asdescribed in U.S. Pat. No. 4,876,248, to Breliere et al., Oct. 24, 1989,which is incorporated by reference herein in its entirety.

1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid(zoledronate).

Nonlimiting examples of bisphosphonates include alendronate,cimadronate, clodronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, pamidronate, piridronate,risedronate, tiludronate, and zolendronate, and pharmaceuticallyacceptable salts and esters thereof. A particularly preferredbisphosphonate is alendronate, especially a sodium, potassium, calcium,magnesium or ammonium salt of alendronic acid. Exemplifying thepreferred bisphosphonate is a sodium salt of alendronic acid, especiallya hydrated sodium salt of alendronic acid. The salt can be hydrated witha whole number of moles of water or non whole numbers of moles of water.Further exemplifying the preferred bisphosphonate is a hydrated sodiumsalt of alendronic acid, especially when the hydrated salt isalendronate monosodium trihydrate.

It is recognized that mixtures of two or more of the bisphosphonateactives can be utilized.

The precise dosage of the organic bisphosphonate will vary with thedosing schedule, the particular bisphosphonate chosen, the age, size,sex and condition of the mammal or human, the nature and severity of thedisorder to be treated, and other relevant medical and physical factors.Thus, a precise pharmaceutically effective amount cannot be specified inadvance and can be readily determined by the caregiver or clinician.Appropriate amounts can be determined by routine experimentation fromanimal models and human clinical studies. Generally, an appropriateamount of bisphosphonate is chosen to obtain a bone resorptioninhibiting effect, i.e. a bone resorption inhibiting amount of thebisphosphonate is administered. For humans, an effective oral dose ofbisphosphonate is typically from about 1.5 to about 6000, μg/kg bodyweight and preferably about 10 to about 2000 μg/kg of body weight. Foralendronate monosodium trihydrate, common human doses which areadministered are generally in the range of about 2 mg/day to about 40mg/day, preferably about 5 mg/day to about 40 mg/day. In the U.S.presently approved dosages for alendronate monosodium trihydrate are 5mg/day for preventing osteoporosis, 10 mg/day for treating osteoporosis,and 40 mg/day for treating Paget's disease.

In alternative dosing regimens, the bisphosphonate can be administeredat intervals other than daily, for example once-weekly dosing,twice-weekly dosing, biweekly dosing, and twice-monthly dosing. In aonce weekly dosing regimen, alendronate monosodium trihydrate would beadministered at dosages of 35 mg/week or 70 mg/week. The bisphosphonatesmay also be administered monthly, ever six months, yearly or even lessfrequently, see WO 01/97788 (published Dec. 27, 2001) and WO 01/89494(published Nov. 29, 2001).

“Estrogen” includes, but is not limited to naturally occurringestrogens, estradiol (E₂), estrone (E₁), and estriol (E₃), syntheticconjugated estrogens, oral contraceptives and sulfated estrogens. See,Gruber C J, Tschugguel W, Schneeberger C, Huber J C., “Production andactions of estrogens” N Engl J Med 2002 January 31 ;346(5):340-52.

“Estrogen receptor modulators” refers to compounds which interfere orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, estrogen, progestogen, estradiol, droloxifene, raloxifene,lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Cathepsin K inhibitors” refers to compounds which interfere with theactivity of the cysteine protease cathepsin K. Nonlimiting examples ofcathepsin K inhibitors can be found in PCT publications WO 00/55126 toAxys Pharmaceuticals and WO 01/49288 to Merck Frosst Canada & Co. andAxys Pharmaceuticals.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“An inhibitor of osteoclast proton ATPase” refers to an inhibitor of theproton ATPase, which is found on the apical membrane of the osteoclast,and has been reported to play a significant role in the bone resorptionprocess. This proton pump represents an attractive target for the designof inhibitors of bone resorption which are potentially useful for thetreatment and prevention of osteoporosis and related metabolic diseases.See C. Farina et al., “Selective inhibitors of the osteoclast vacuolarproton ATPase as novel bone antiresorptive agents,” DDT, 4: 163-172(1999)), which is hereby incorporated by reference in its entirety.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for HBG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938,4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos.4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S.Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589),fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165,4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatinLIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and5,342,952) and cerivastatin (also known as rivastatin and BAYCHOL®; seeU.S. Pat. No. 5,177,080). The structural formulas of these andadditional HMG-CoA reductase inhibitors that may be used in the instantmethods are described at page 87 of M. Yalpani, “Cholesterol LoweringDrugs”, Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

In HMG-CoA reductase inhibitors where an open-acid form can exist, saltand ester forms may preferably be formed from the open-acid, and allsuch forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin. Herein, the term “pharmaceutically acceptablesalts” with respect to the HMG-CoA reductase inhibitor shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, and tris(hydroxymethyl) aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but are notlimited to, acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynapthoate, iodide, isothionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamaote,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-COA reductase inhibitor compoundsmay act as prodrugs which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

As used herein, “cholesterol ester transfer protein inhibitor” refers toan inhibitor of cholesterol ester transfer protein (CETP), a plasmaprotein that mediates the exchange of cholesteryl ester in high-densitylipoprotein (HDL) for triglycerides in very low density lipoprotein(VLDL). A non-limiting example of a CETP inhibitor is torcetrapib.

As used above, “integrin receptor antagonists” refers to compounds whichselectively antagonize, inhibit or counteract binding of a physiologicalligand to the α_(v)β₃ integrin, to compounds which selectivelyantagonize, inhibit or counter-act binding of a physiological ligand tothe αvβ5 integrin, to compounds which antagonize, inhibit or counteractbinding of a physiological ligand to both the α_(v)β₃ integrin and theα_(v)β₅ integrin, and to compounds which antagonize, inhibit orcounteract the activity of the particular integrin(s) expressed oncapillary endothelial cells. The term also refers to antagonists of theα_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. The termalso refers to antagonists of any combination of α_(v)β₃, α_(v)β₅,α_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄ integrins. H. N.Lode and coworkers in PNAS USA 96: 1591-1596 (1999) have observedsynergistic effects between an antiangiogenic αv integrin antagonist anda tumor-specific antibody-cytokine (interleukin-2) fusion protein in theeradication of spontaneous tumor metastases. Their results suggestedthis combination as having potential for the treatment of cancer andmetastatic tumor growth. α_(v)β₃ integrin receptor antagonists inhibitbone resorption through a new mechanism distinct from that of allcurrently available drugs. Integrins are heterodimeric transmembraneadhesion receptors that mediate cell-cell and cell-matrix interactions.The α and β integrin subunits interact non-covalently and bindextracellular matrix ligands in a divalent cation-dependent manner. Themost abundant integrin on osteoclasts is α_(v)β₃ (>10⁷/osteoclast),which appears to play a rate-limiting role in cytoskeletal organizationimportant for cell migration and polarization. The α_(v)β₃ antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of macular degeneration, inhibition of arthritis,and inhibition of cancer and metastatic growth.

“An osteoblast anabolic agent” refers to agents that build bone, such asPTH. The intermittent administration of parathyroid hormone (PTH) or itsamino-terminal fragments and analogues have been shown to prevent,arrest, partially reverse bone loss and stimulate bone formation inanimals and humans. For a discussion refer to D. W. Dempster et al.,“Anabolic actions of parathyroid hormone on bone,” Endocr Rev 14:690-709 (1993). Studies have demonstrated the clinical benefits ofparathyroid hormone in stimulating bone formation and thereby increasingbone mass and strength. Results were reported by R M Neer et al., in NewEng J Med 344 1434-1441 (2001).

In addition, parathyroid hormone-related protein fragments or analogues,such as PTHrP-(1-36) have demonstrated potent anticalciuric effects [seeM. A. Syed et al., “Parathyroid hormone-related protein-(1-36)stimulates renal tubular calcium reabsorption in normal humanvolunteers: implications for the pathogenesis of humoral hypercalcemiaof malignancy,” JCEM 86: 1525-1531 (2001)] and may also have potentialas anabolic agents for treating osteoporosis.

Calcitonin is a 32 amino acid pepetide produced primarily by the thyroidwhich is known to participate in calcium and phosphorus metabolism.Calcitonin suppresses resorption of bone by inhibiting the activity ofosteoclasts. Thus, calcitonin can allow osteoblasts to work moreeffectively and build bone.

“Vitamin D” includes, but is not limited to, vitamin D₃(cholecalciferol) and vitamin D₂ (ergocalciferol), which are naturallyoccurring, biologically inactive precursors of the hydroxylatedbiologically active metabolites of vitamin D: lo-hydroxy vitamin D;25-hydroxy vitamin D, and 1α,25-dihydroxy vitamin D. Vitamin D₂ andvitamin D₃ have the same biological efficacy in humans. When eithervitamin D₂ or D₃ enters the circulation, it is hydroxylated bycytochrome P₄₅₀-vitamin D-25-hydroxylase to give 25-hydroxy vitamin D.The 25-hydroxy vitamin D metabolite is biologically inert and is furtherhydroxylated in the-kidney by cytochrome P450-monooxygenase, 25 (OH)D-1α-hydroxylase to give 1,25-dihydroxy vitamin D. When serum calciumdecreases, there is an increase in the production of parathyroid hormone(PTH), which regulates calcium homeostasis and increases plasma calciumlevels by increasing the conversion of 25-hydroxy vitamin D to1,25-dihydroxy vitamin D.

1,25-dihydroxy vitamin D is thought to be reponsible for the effects ofvitamin D on calcium and bone metabolism. The 1,25-dihydroxy metaboliteis the active hormone required to maintain calcium absorption andskeletal integrity. Calcium homeostasis is maintained by 1,25 dihydroxyvitamin D by inducing monocytic stem cells to differentiate intoosteoclasts and by maintaining calcium in the normal range, whichresults in bone mineralization by the deposition of calciumhydroxyapatite onto the bone surface, see Holick, M F, Vitamin Dphotobiology, metabolism, and clinical applications, In: DeGroot L,Besser H, Burger H G, eg al., eds. Endocrinology, 3^(rd) ed., 990-1013(1995). However, elevated levels of 1α,25-dihydroxy vitamin D₃ canresult in an increase of calcium concentration in the blood and in theabnormal control of calcium concentration by bone metabolism, resultingin hypercalcemia. 1α,25-dihydroxy vitamin D₃ also indirectly regulatesosteoclastic activity in bone metabolism and elevated levels may beexpected to increase excessive bone resorption in osteoporosis.

“Synthetic vitamin D analogues” includes non-naturally occurringcompounds that act like vitamin D.

As used herein, the term “aromatase inhibitor” refers to an inhibitor ofaromatase, an enzyme which effects the aromatasation of ring A in themetabolic formation of various steroid hormones. Various cancers, forexample breast cancer, and other disorders are dependent uponcirculating steroid hormones which have an aromatic ring A. By removingthe source of ring A hormones, such cancers and other disorders can betreated. Nonlimiting examples of aromatase inhibitors includeanastrozole, letrozole and exemestane.

Selective Serotonin Reuptake Inhibitors act by increasing the amount ofserotonin in the brain. SSRIs have been used successfully for a decadein the United States to treat depression. Non-limiting examples of SSRIsinclude fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine.SSRIs are also being used to treat disoreders realted to estrogenfunctioning, suchs as premenstrual syndrome and premenstrual dysmorphicdisorder. See Sundstrom-Poromaa I, Bixo M, Bjorn I, Nordh O.,“Compliance to antidepressant drug therapy for treatment of premenstrualsyndrome,” J Psychosom Obstet Gynaecol 2000 December; 21(4):205-11.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The term “admninistration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a bisphosphonate, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents. The present inventionincludes within its scope prodrugs of the compounds of this invention.In general, such prodrugs will be functional derivatives of thecompounds of this invention which are readily convertible in vivo intothe required compound. Thus, in the methods of treatment of the presentinvention, the term “administering” shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985, which is incorporated byreference herein in its entirety. Metabolites of these compounds includeactive species produced upon introduction of compounds of this inventioninto the biological milieu.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of osteoporosis or other bone disorders,comprising the administration of a therapeutically effective amount ofthe compounds of this invention, with or without pharmaceuticallyacceptable carriers or diluents. Suitable compositions of this inventioninclude aqueous solutions comprising compounds of this invention andpharmacologically acceptable carriers, e.g., saline, at a pH level,e.g., 7.4. The solutions may be introduced into a patient's bloodstreamby local bolus injection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment. Oral dosages of thepresent invention, when used for the indicated effects, will rangebetween about 0.01 mg per kg of body weight per day (mg/kg/day) to about100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1to 5.0 mg/kg/day. For oral administration, the compositions arepreferably provided in the form of tablets containing 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. A medicament typically contains from about0.01 mg to about 500 mg of the active ingredient, preferably, from about1 mg to about 100 mg of active ingredient. Intravenously, the mostpreferred doses will range from about 0.1 to about 10 mg/kg/minuteduring a constant rate infusion. Advantageously, compounds of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. Furthermore, preferred compounds for the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittant throughout the dosage regimen.

The compounds of the present invention can be used in combination withother agents useful for treating estrogen-mediated conditions. Theindividual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating cathepsin-mediated conditions includes in principle anycombination with any pharmaceutical composition useful for treatingdisorders related to estrogen functioning.

The scope of the invetion therefore encompasses the use of the instantlyclaimed compounds in combination with a second agent selected from: anorganic bisphosphonate; a cathepsin K inhibitor; an estrogen; anestrogen receptor modulator; an androgen receptor modulator; aninhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoAreductase; an integrin receptor antagonist; an osteoblast anabolicagent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; aselective serotonin reuptake inhibitor; an aromatase inhibitor; and thepharmaceutically acceptable salts and mixtures thereof.

These and other aspects of the invention will be apparent from theteachings contained herein.

DEFINITIONS

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The terms “treating” or “treatment” of a disease as used hereinincludes: preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease; inhibiting the disease, i.e., arresting orreducing the development of the disease or its clinical symptoms; orrelieving the disease, i.e., causing regression of the disease or itsclinical symptoms.

The term “bone resorption,” as used herein; refers to the process bywhich osteoclasts degrade bone.

The term “basic conditions,” as used herein, refers to the incorporationor use of a base in the reaction medium. According to the Lowry-Bronsteddefinition, a base is a substance that accepts a proton; or according tothe Lewis definition, a base is a substance that can furnish an electronpair to form a covalent bond. Examples of bases used herein, but are notlimited to, are tertiary amine bases such as triethylamine,diisopropylethylamine, or the like.

The term “acidic conditions,” as used herein, refers to theincorporation or use of an acid in the reaction medium. According to theLowry-Bronsted definition, an acid is a substance that gives up aproton; or according to the Lewis definition, an acid is a substancethat can take up an electron pair to form a covalent bond. Examples ofacids used herein, but are not limited to, are strong carboxylic acidssuch as trifluoroacetic acid, or the like, strong sulfonic acids, suchas trifluoromethane sulfonic acid, or the like, and Lewis acids, such asboron trifluoride etherate, or stannous chloride, or the like.

The term “reducing agent,” as used herein, refers to a reagent capableof performing a reduction. A reduction is the conversion of a functionalgroup or an intermediate from one category to a lower one. Examples ofreducing agents used herein, but are not limited to, aretriorganosilanes or stannanes, such as triethylsilane, triphenylsilane,and tri-n-butyl tin hydride, or the like. Other common reducing agentsinclude, but are not limited to hydrogen, Raney Nickel, lithium aluminumhydride, diisobutylaluminum hydride, and the like.

The term “chemically differentiable” refers to two or more non-identicalR⁶ substituents whose unique structures are such that one of ordinaryskill in the art could choose reaction conditions which would convertone of the non-identical R⁶ substituents to H, without affecting theother R⁶ substituent.

As used herein, “alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms. For example, C₁-C₁₀, as in “C₁-C₁₀alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 carbons in a linear or branched arrangement. For example, “C₁-C₁₀alkyl” specifically includes methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, and so on. “Alkoxy” represents analkyl group of indicated number of carbon atoms attached through anoxygen bridge.

As appreciated by those of skill in the art, “halo” or “halogen” as usedherein is intended to include chloro, fluoro, bromo and iodo.

The term “hydroxyalkyl” means a linear monovalent hydrocarbon raidcal ofone to six carbon atoms or a branched monovalent hydrocarbon radical ofthree to six carbons substituted with one or two hydroxyl groups,provided that if two hydroxyl groups are present they are not both onthe same carbon atom. Representative examples include, but are notlimited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, and the like.

The present invention also includes N-oxide derivatives and protectedderivatives of compounds of Formula I. For example, when compounds ofFormula I contain an oxidizable nitrogen atom, the nitrogen atom can beconverted to an N-oxide by methods well known in the art. Also whencompounds of Formula I contain groups such as hydroxyl, carboxy, thiolor any group containing a nitrogen atom(s), these groups can beprotected with a suitable protecting groups. A comprehensive list ofsuitable protective groups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1981, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of Formula I can be prepared bymethods well known in the art.

The alkyl substituents may be unsubstituted or unsubstituted, unlessspecifically defined otherwise. For example, a (C1-C6)alkyl may besubstituted with one or more substituents selected from OH, oxo,halogen, alkoxy, dialkylamino, or heterocyclyl, such as morpholinyl,piperidinyl, and so on. In the case of a disubstituted alkyl, forinstance, wherein the substituents are oxo and OH, the following areincluded in the definition: —(C═O)CH₂CH(OH)CH₃, —(C═O)OH,—CH₂(OH)CH₂CH(O), and so on.

The term “triorganosilyl” means those silyl groups trisubstituted bylower alkyl groups or aryl groups or combinations thereof and whereinone substituent may be a lower alkoxy group. Examples of triorganosilylgroups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl,triisopropylsilyl, triphenylsilyl, dimethylphenylsilyl,t-butyldiphenylsilyl, phenyl-t-butylmethoxysilyl and the like.

In the compounds of the present invention, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, heterocyclyl and heteroaryl groups can befurther substituted by replacing one or more hydrogen atoms bealternative non-hydrogen groups. These include, but are not limited to,halo, hydroxyl, mercapto, amino, carboxy, cyano and carbamoyl.

The term “oxy” means an oxygen (0) atom. The term “thio” means a sulfur(S) atom. The term “oxo” means ═O. The term “oximino” means the ═N—Ogroup. The term “keto” means carbonyl (C═O). The term “thiocynanto”refers to —SCN.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, NewYork, 1994, pages 1119-1190), and occur as racemates, racemic mixtures,and as individual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein may exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof.

When any variable (e.g. R¹, R², R³ etc.) occurs more than one time inany constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents indicate that theindicated bond may be attached to any of the sub-stitutable ring carbonatoms. If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to three substituents.

Under standard nonmenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅ alkylcarbonylamino C₁₋₆ alkyl substituent isequivalent to

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², R³,are to be chosen in conformity with well-known principles of chemicalstructure connectivity.

Representative compounds of the present invention typically displaysubmicromolar affinity for alpha and/or beta estrogen receptors.Compounds of this invention are therefore useful in treating mammalssuffering from disorders related to estrogen functioning.

The compounds of the present invention are available in racemic form oras individual enantiomers. For convenience, some structures aregraphically represented as a single enantiomer but, unless otherwiseindicated, is meant to include both racemic and enantiomerically pureforms. Where cis and trans stereochemistry is indicated for a compoundof the present invention, it should be noted that the stereochemistryshould be construed as relative, unless indicated otherwise. Forexample, a (+) or (−) designation should be construed to represent theindicated compound with the absolute stereochemistry as shown.

Racemic mixtures can be separated into their individual enantiomers byany of a number of conventional methods. These include, but are notlimited to, chiral chromatography, derivatization with a chiralauxiliary followed by separation by chromatography or crystallization,and fractional crystallization of diastereomeric salts. Deracemizationprocedures may also be employed, such as enantiomeric protonation of apro-chiral intermediate anion, and the like.

The compounds of the present invention can be used in combination withother agents useful for treating estrogen-mediated conditions. Theindividual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating estrogen-mediated conditions includes in principle anycombination with any pharmaceutical composition useful for treatingdisorders related to estrogen functioning.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed inorganic or organic acids. For example,conventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like, as well as salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxylmaleic,phenylacetic, glutamic, benzoic, salicylic, sulfanilic,2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, trifluoroacetic and the like. Thepreparation of the pharmaceutically acceptable salts described above andother typical pharmaceutically acceptable salts is more fully describedby Berg et al., “Pharmaceutical Salts,” J. Pharm. Sci., 1977:66:1-19,hereby incorporated by reference. The pharmaceutically acceptable saltsof the compounds of this invention can be synthesized from the compoundsof this invention which contain a basic or acidic moiety by conventionalchemical methods. Generally, the salts of the basic compounds areprepared either by ion exchange chromatography or by reacting the freebase with stoichiometric amounts or with an excess of the desiredsalt-forming inorganic or organic acid in a suitable solvent or variouscombinations of solvents. Similarly, the salts of the acidic compoundsare formed by reactions with the appropriate inorganic or organic base.

The novel compounds of the present invention can be prepared accordingto the following general schemes, using appropriate materials, and arefurther exemplified by the subsequent specific examples. The compoundsillustrated in the examples are not, however, to be construed as formingthe only genus that is considered as the invention. Those skilled in theart will readily understand that known variations of the conditions andprocesses of the following preparative procedures can be used to preparethese compounds. All temperatures are degrees Celsius unless otherwisenoted.

For purposes of this specification, the following abbreviations have theindicated meanings: Bn = benzyl CHCl₃ = chloroform CuSO₄ = coppersulfate DIAD = diisopropylazodicarboxylate DMAP =4-(dimethylamino)pyridine DMF = N,N-dimethylfonnamide DMSO =dimethylsulfoxide Et₃N = triethylamine EtOAc = ethyl acetate EtOH =ethanol HOAc = acetic acid K₂CO₃ = potassium carbonate MeOH = methanolMOM = methoxymethyl MgSO₄ = magnesium sulfate Na₂CO₃ = sodium carbonateNaHCO₃ = sodium bicarbonate NaOH = sodium hydroxide Na₂SO₄ = sodiumsulfate NH₄Cl = ammonium chloride Pd/C = palladium on carbon PPh₃ =triphenylphosphine PPA = polyphosphoric acid PTAB =trimethylammoniumphenyl perbromide Py = pyridine rt = room temperaturesat. aq. = saturated aqueous TBAF = Tetrabutylammonium fluoride TFA =trifluoroacetic acid THF = tetrahydrofuran TIPS = triisopropyl tlc =thin layer chromatography Me = methyl Et = ethyl n-Pr = normal propyli-Pr = isopropyl n-Bu = normal butyl i-Bu = isobutyl s-Bu = secondarybutyl t-Bu = tertiary butylThe compounds of the present invention can be prepared according to thefollowing Schemes I, II, and III

In words relative to Scheme I, an appropriately functionalizedphenylacetophenone derivative, which can be prepared according to thedepicted literature process, can be converted to an appropriatelyfunctionalized bromo-phenylacetophenone derivative by bromination withphenyltrimethylammonium tribromide (PTAB). In turn, the bromide can bereacted with an appropriately functionalized mercapto-phenol derivative,which can be prepared according to literature procedures, in thepresence of a tertiary amine base, such as triethylamine,diisopropylethylamine, or the like, in a solvent such asdimethylformamide (DMF), formamide, acetonitrile, dimethylsulfoxideDMSO), tetrahydrofuran THF) dichloromethane, or the like, at atemperature of from −20° C. to 80° C. for as long as it takes for thereaction to complete to provide the displacement product.

This intermediate can be reductively cyclized in the presence of anorganic acid such as trriluoroacetic acid, triflic acid, or the like, ora Lewis acid such as boron trifluoride etherate, stannous chloride, orthe like, and a reducing agent such as a trisubstituted silane, suchtriethylsilane, or the like, in a solvent such as dichloromethane,chloroform, THF, toluene, or the like at a temperature of from −40° C.to 100° C. for as long as it takes for the reaction to complete toprovide the cyclized dihydro-benzoxathiin, in which the stereochemistryof the aryl substituents in the newly created ring is exclusively cis.

The alcohol intermediate can be conveniently resolved at this point bychiral chromatography into both optical antipodes. The positivelyrotating isomer having the (2S, 3R) absolute configuration, depicted inScheme II, can then be reacted with a chiral pyrrolidino-ethanolderivatives such as HOCH₂CH(CH₃)NZ₂, or the like, wherein, NZ₂represents pyrrolidine, which may also be substituted, in a Mitsunobureaction protocol, in which they are combined with a trisubstitutedphosphine, such as triphenylphosphine and a diazodicarboxylate, such asdiisopropylazodicarboxylate, in a suitable solvent such as THF at from0° C. to 80° C. for as long as it takes for the reaction to complete toprovide the coupled product. In addition, it should be noted that thisMitsunobu reaction proceeds through a spiro-aziridinium intermediatewhich typically results in the formation of two products: the “normal”addition product, and the “rearranged” product, which places the chiralcenter at the other carbon of the linker chain, ie, next to the oxygenatom. The variables for the Mitsunobu reaction have been well documentedand are incorporated herein by reference: Mitsunobu, O. Synthesis, 1981,1; Castro, B. R. Org. React. 1983, 29, 1; Hughes, D. L. Org. React.1992, 42, 335. Finally, after the Mitsunobu reaction, the protectinggroups can be sequentially removed, from either product, utilizing theappropriate method which may be found in such standard references as:Greene, T. W. and Wuts, P. G. M., Protective Groups in OrganicSynthesis, Third Ed.,Wiley, New York (1999), to give the final productsof the invention. Further, it is also understood, that the foregoingchemistry can also be performed with racemic materials as well.

Alternatively, it is possible to eliminate the rearranged productdepicted in Scheme II, by utilization of a different chemical processwhich is oulined in Scheme III. Thus, as previously described in SchemeI, an appropriately functionalized dihydrobenzoxathiin intermediatepossessing an iodo group in the pendant phenyl ring can be prepared, andreacted with the selected hydroxyethylpyrrolidine derivative in acopper-catalyzed coupling reaction in a manner as described in theliterature, eg. Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L.Org. Letters, 2002, 4, 973. The unmasking of the phenolic groups canthen be achieved as previously stated. Further, it is also understood,that the foregoing chemistry can also be performed with chiral materialsas well.

ASSAYS

The utility of the compounds of the instant invention can be readilydetermined by methods well known to one of ordinary skill in the art.These methods may include, but are not limited to, the assays describedin detail below. The compounds of the instant invention were tested inthe following assays and found to have the relevant activity.

Estrogen Receptor Binding Assay

The estrogen receptor ligand binding assays are designed asscintillation proximity assays employing the use of tritiated estradioland recombinant expressed estrogen receptors. The full lengthrecombinant human ER-α and ER-β proteins are produced in a bacculoviralexpression system. ER-α or ER-β extracts are diluted 1:400 in phosphatebuffered saline containing 6 mM α:-monothiolglycerol. 200 μL aliquots ofthe diluted receptor preparation are added to each well of a 96-wellFlashplate. Plates are covered with Saran Wrap and incubated at 4° C.overnight. The following morning, a 20 ul aliquot of phosphate bufferedsaline containing 10% bovine serum albumin is added to each well of the96 well plate and allowed to incubate at 4° C. for 2 hours. Then theplates are washed with 200 ul of buffer containing 20 mM Tris (pH 7.2),1 mM EDTA, 10% Glycerol, 50 mM KCl, 5 and 6 mM α-monothiolglycerol. Toset up the assay in these receptor coated plates, add 178 ul of the samebuffer to each well of the 96 well plate. Then add 20 ul of a 10 nMsolution of ³H-estradiol to each well of the plate.

Test compounds are evaluated over a range of concentrations from 0.01 nMto 1000 nM. The test compound stock solutions should be made in 100%DMSO at 100× the final concentration desired for testing in the assay.The amount of DMSO in the test wells of the 96 well plate should notexceed 1%. The final addition to the assay plate is a 2 ul aliquot ofthe test compound which has been made up in 100% DMSO. Seal the platesand allow them to equilibrate at room temperature for 3 hours. Count theplates in a scintillation counter equipped for counting 96 well plates.

Ovariectomized Rat Assay

In the ovariectomized (OVX) Rat Assay, estrogen-deficiency is used toinduce cancellous osteopenia (e.g. low bone mineral density [BMD;mg/cm²]), associated with accelerated bone resorption and formation.Both the BMD and bone resorption/formation outcomes are used to modelthe changes in bone that occur as women pass through menopause. The OVXRat Assay is the principal in vivo assay used by all major academic andindustrial laboratories studying the efficacy of new chemical entitiesin preventing estrogen-deficiency bone loss.

Sprague-Dawley female rats aged 6-8 months are OVXd and, within 24hours, started on treatment for 42 days with vehicle or multiple dosesof test compound. Untreated sham-OVX and alendronate-treated (0.003mg/kg s.c., q.d.) or 17-β-estradiol-treated (0.004 mg/kg s.c., q.d.)groups are included as positive controls. Test compounds may beadministered orally, subcutaneously, or by infusion throughsubcutaneously-implanted minipump. Before necropsy, in vivo duallabeling with calcein (8 mg/kg by subcutaneous injection), a boneseeking fluorochrome, is completed. At necropsy, blood, femurs, avertebral body segment, and the uterus, are obtained.

The routine endpoints for the OVX Rat Assay include assessments of bonemass, bone resorption, and bone formation. For bone mass, the endpointis BMD of the distal femoral metaphysis, a region that contains about20% cancellous bone. The vertebral segment, a region with ˜25%cancellous bone may also be used for BMD determination. The BMDmeasurement is made by dual energy x-ray absorptiometry (DXA, Hologic4500A; Waltham, Mass.). For bone resorption, the endpoint is urinarydeoxypyridinoline crosslinks, a bone collagen breakdown product (uDPD;expressed as nM DPD/nM creatinine). This measurement is made with acommercially available kit (Pyrilinks; Metra Biosystems, Mountain View,Calif.). For bone formation, the endpoints are mineralizing surface andmineral apposition rate, histomorphometric measures of osteoblast numberand activity. This measurement is done on 5 μm sections of thenon-decalcified proximal tibial metaphysis, using a semi-automatedsystem (Bioquant; R&M Biometrics; Nashyille, Tenn.). Similar endpointsand measuring techniques for each endpoint are commonly used inpostmenopausal women.

Rat Cholesterol Lowering Assay

Sprague-Dawley rats (5 per group) weighing about 250 g weresubcutaneously dosed with compounds of the present invention dissolvedin propylene glycol for 4 days. A group of 5 rats was dosed with vehicleonly. On the fifth day, rats were euthanized with carbon dioxide andtheir blood samples were obtained. Plasma levels of cholesterol wereassayed from these samples with commercially available cholesteroldetermination kits from Sigma.

MCF-7 Estrogen Dependent Proliferation Assay

MCF-7 cells (ATCC #HTB-22) are human mammary gland adenocarcinoma cellsthat require estrogen for growth. The growth media (GM) for the MCF-7cells is Minimum Essential Media (without phenol red) supplemented withfetal bovine serum (FBS) to 10%. The FBS serves as the sole source ofestrogen and this GM supports the full growth of the cells and is usedfor the routine growth of the cell cultures. When MCF-7 cells are placedin a media in which 10% Charcoal-Dextran treated fetal bovine serum(CD-FBS) is substituted for FBS, the cells will cease to divide but willremain viable. The CD-FBS does not contain detectable levels of estrogenand the media containing this sera is referred to as Estrogen DepletedMedia (EDM). The addition of estradiol to EDM stimulates the growth ofthe MCF-7 cells in a dose dependent manner with an EC₅₀ of 2 pM.

Growing MCF-7 cells are washed several times with EDM and the culturesthen maintained in EDM for a minimum of 6 days in order to deplete thecells of endogenous estrogen. On day 0 (at the startof the assay), theseestrogen depleted cells are plated into 96-well cell culture plates at adensity of 1000 cells/well in EDM in a volume of 180 ul/well. On day 1test compounds are diluted in a 10-fold dilution series in EDM and 20 ulof these dilutions added to the 180 ul of media in the appropriate wellof the cell plate resulting in a further 1:10 dilution of the testcompounds. On days 4 and 7 of the assay, the culture supernatant isaspirated and replaced with fresh EDM and test compound dilutions asabove. The assay is terminated at day 8-10 when the appropriate controlsreach 80-90% confluency. At this point, the culture supernatants areaspirated, the cells washed 2× with PBS, the wash solution aspirated andthe protein content of each well determined. Each drug dilution isevaluated on a minimum of 5 wells and the range of dilution of the testcompounds in the assay is 0.001 nM to 1000 nM. The assay in the aboveformat is employed to determine the estradiol agonist potential of atest compound.

In order to evaluate the antagonist activity of a test compound, theMCF-7 cells are maintained in EDM for a minimum of 6 days. Then on day 0(at the start of the assay), these estrogen depleted cells are platedinto 96-well cell culture plates at a density of 1000 cells/well in EDMin a volume of 180 ul/well. On day 1 the test compounds in fresh mediacontaining 3 pM estradiol are applied to the cells. On days 4 and 7 ofthe assay, the culture supernatant is aspirated and replaced with freshEDM containing 3 pM estradiol and the test compound. The assay isterminated at day 8-10 when the appropriate controls reach 80-90%confluency and the protein content of each well is determined as above.

Rat Endometriosis Model

Animals:

-   Species: Rattus norvegicus-   Strain: Sprague-Dawley CD-   Supplier: Charles River Laboratories, Raleigh, N.C.-   Sex: Female Weight: 200-240 gram    Rats are single-housed in polycarbonate cages and are provided    Teklad Global Diet 2016 (Madison, Wis.) and bottled reverse osmosis    purified H2O ad libitum. They are maintained on a 12/12 light/dark    cycle.

Rats are anesthetized with Telazo™ (20 mg/kg, ip) and oxymorphone (0.2mg/kg sc) and positioned dorsoventrally on a sterile drape. Bodytemperature is maintained using a underlying circulating water blanket.The surgical sites are shaved with clippers and cleaned using threecycles of betadine/isopropyl alcohol or Duraprep® (3M). The incisionalarea is covered with a sterile drape.

Using aseptic technique, a 5 cm midline lower abdominal incision is madethrough the skin, subcutaneous and muscle layers. A bilateralovariectomy is performed. The left uterine blood vessels are ligated anda 7 mm segment of the left uterine horn is excised. The uterus is closedwith 4-0 gut suture. The myometrium is aseptically separated from theendometrium and trimmed to 5×5 mm. The trimmed section of theendometrium is transplanted to the ventral peritoneal wall with theepithelial lining of the segment opposed to the peritoneal wall. Theexplanted endometrial tissue is sutured at its four corners to the bodywall using sterile 6-0 silk. The abdominal muscular layer is closedusing sterile 4-0 chromic gut. The skin incision is closed using sterilestainless surgical clips. A sterile 90-day sustained release estrogenpellet (Innovative Research of America, 0.72 ng/pellet; circulatingestrogen equivalent of 200-250 pg/mL) is implanted subcutaneously in thedorsal lateral scapular area. A sterile implantable programmabletemperature transponder (RPTM) (BMDS, Seaford, Del.) is injectedsubcutaneously in the dorsoscapular region. The rats are observed untilfully ambulatory, and allowed to recover from surgery undisturbed for 3weeks.

Three weeks after transplantation of the endometrial tissue, the animalsundergo a repeat laparotomy using aseptic surgical site preparation andtechnique. The explant is evaluated for graft acceptance, and the areais measured with calipers and recorded. The animals with rejected graftsare removed from the study. Animals are sorted to create similar averageexplant volume per group.

Drug or vehicle(control) treatment is initiated one day after the secondlaparotomy and continued for 14 days. Body temperature is recorded everyother day at 10:00 am using the BMDS scanner.

At the end of the 14 day treatment period, the animals are euthanized byCO₂ overdose. Blood is collected by cardiocentesis for circulatingestrogen levels. The abdomen is opened, the explant is examined,measured, excised, and wet weight is recorded. The right uterine horn isexcised, and wet and dry weights are recorded.

EXAMPLES Example 1 Preparation of 4-Benzyloxy-2-Mercapto-Phenol

Step A:

To a solution of thiourea (26.66 g, 0.35 moles) in 2 N hydrochloric acid(350 mL) was added a solution of 1,4-benzoquinone (25.04 g, 0.23 moles)in acetic acid (350 mL) via a dropping funnel. The resulting ambersolution was stirred at ambient temperature for 35 min., then heated to110° C. for 3 h under nitrogen. The reaction was cooled in an ice bathat which time, a pale lavender solid precipitated out of solution. Theresulting mixture was stored at 0° C. for 16 h. The precipitate wascollected by vacuum filtration and redissolved in ethyl acetate. Theethyl acetate solution was washed with brine, dried over sodium sulfate,and concentrated in vacuo to give the desired product as a pale lavendersolid. ¹H NMR (500 MHz, CDCl₃) δ (ppm): 5.05 (bs, 1H), 6.80 (dd, 1H),6.93 (d, 1H), 7.19 (d, 1H).

Step B:

To a solution of the thiocarbonate from Step A (17.47 g, 0.10 moles) inanhydrous DMF (200 mL) at 0° C. was added cesium carbonate (54.30 g,0.16 moles) under nitrogen followed by benzyl bromide (14.8 mL, 0.12moles). The reaction became a dark green mixture. After 1 h,approximately 10-20% of the starting material remained. The reaction wasallowed to stir for an additional 1 h, before partitioning the reactionbetween ethyl acetate and ice water. The organic layer was collected,washed with water and brine, dried over sodium sulfate, and concentratedin vacuo to afford a dark brown oil. The residue was purified by silicagel chromatography with 10% ethyl acetate in hexanes as the eluant togive the desired product as a white solid. ¹H NMR (500 MHz, CDCl₃) δ(ppm): 5.08 (s, 2H), 6.95 (dd, 1H), 7.02 (d, 1H), 7.21 (d, 1H),7.36-7.43 (m, 5H).

Step C:

A solution of the protected thiocarbonate (15.10 g, 59 mmol) from Step Bin 100 mL of tetrahydrofuran and 50 mL of ethanol was sparged withnitrogen for 20 min. before adding 5 N sodium hydroxide (47 mL, 233mmol). The reaction was stirred at ambient temperature with continuousnitrogen bubbling. After 1 h, the reaction was cooled to 0° C. and 2 Nhydrochloric acid (116 mL, 233 mmol) was added. The resulting pale greenreaction mixture was extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over sodium sulfate, andconcentrated in vacuo to give a pale green/yellow solid. ¹H NMR (500MHz, CD₃OD) δ (ppm): 4.9 (s, 2H), 688 (d, 1H), 6.96 (d, 1H), 7.04 (dd,1H), 7.3-7.4 (m, 5H)

Example 2 Preparation of 2-Fluoro-3-Mercapto-Hydroquinone

Step A:

A 3-neck 1-liter flask equipped with a low temperature thermometer, N₂line, and dropping funnel was charged with 1,4-dimethoxy-2-fluorobenzene(20.42 g, 131 mmol). The solid was dissolved in distilled TBF (450 mL)and cooled to an internal temperature of −74° C. A 2.5 M solution ofn-BuLi in hexane (63 mL, 157 mmol) was subsequently added over 25 min.under N₂ via a dropping funnel. The reaction was maintained at −75° C.for 30 min., before adding solid sulfur (5.01 g, 157 mmol) in oneportion. Nitrogen sparging of the reaction mixture was begun at thistime and continued throughout the reaction. The internal temperaturerose to −65° C. but quickly recooled to −75° C. The reaction temperaturewas maintained at −75° C. for 30 min. At this time, the excess dry icein the dry ice/acetone bath was removed and the reaction was allowed toslowly warm to −20° C. over 1.5 h. The reaction was quenched with 2 NHCl with vigorous N₂ bubbling until the color of the reaction turnedpale yellow. The internal temperature of the reaction rose to 10° C. Thereaction was extracted with EtOAc. The organic layer was collected,washed with brine, dried over MgSO₄, filtered, and concentrated invacuo. The yellow residue was purified by silica gel chromatography with20% EtOAc/hexane as the eluant to give the desired product as a lightyellow solid. ¹H 600 MHz NMR(CDCl₃) ppm(δ): 3.84 (s, 3H), 3.86 (s, 3H),6.56 (dd, J=1.8 Hz, J=8.9 Hz, 1H), 6.70 (t, 1H).

Step B:

To a solution of the thiophenol (10.66 g, 57 mmol) generated in Step Ain CH₂Cl₂ (100 mL) at 0° C. under N₂ was added a 1 M solution of BBr₃ inCH₂Cl₂ (227 mL, 227 mmol) via a dropping funnel over 10 min. Thereaction solution was continuously sparged with N₂. After stirring at 0°C. for 1 h, the reaction was quenched slowly with cold 2 N HCl. Theresulting mixture was extracted with EtOAc. The organic layer wascollected, washed with brine, dried over Na₂SO₄, filtered, andconcentrated in vacuo. The resulting light purple solid was used withoutfurther purification. ¹H 600 MHz NMR(CD30D) ppm(δ): 6.42 (dd, J=1.8 Hz,J=8.9 Hz, 1H), 6.51 (t, 1H).

Example 2A Preparation of

Step A:

To a solution of the crude fluoromercaptan (12 mmol) from Example 2 inanhydrous THF (25 mL) was added 1,1′-carbonyldiimidazole (3.9 g, 24mmol) at ambient temperature with nitrogen sparging, followed by acatalytic amount of DMAP. The reaction was stirred for 10 min., thenpartitioned between ethyl acetate and ice/2 N HCl. The organic layer wascollected, washed with brine, dried over sodium sulfate, andconcentrated in vacuo to give a pale yellow solid. Purification bysilica gel chromatography with 15% ethyl acetate/hexane as the eluantafforded the desired product as a white solid (1.91 g, 83%). ¹H 500 MHzNMR(CDCl₃) ppm(δ): 7.00-7.02 (m, 2 H).

Step B:

To a solution of the material obtained from Step A (1.91 g, 10 mmol) inanhydrous DMF (20 mL), was added cesium carbonate (6.7 g, 21 mmol) at 0°C. under nitrogen followed by benzyl bromide (1.5 mL, 12 mmol). After2.5 h of vigorous stirring, the reaction was filtered to remove thecesium carbonate. The filtrate was partitioned between ethyl acetate and2 N HCl/ice. The organic layer was further washed with brine, dried oversodium sulfate, and concentrated in vacuo. Purification by silica gelchromatography with 15% ethyl acetate/hexane as the eluant gave thedesired product (1.1709 g, 42%). 1H 500 MHz NMR(CDCl3) ppm(δ): 5.19 (s,2H), 7.00-7.02 (m, 2H), 7.36-7.44 (m, 5H).

Step C:

Utilizing the procedure outlined in Example 1, Step C, the thiocarbonate(1.1709 g, 4.2 mmol) was converted to the free thiol. The crude materialwas used without further purification. ¹H 500 MHz NMR(CDCl₃) ppm(δ):5.09 (s, 2H), 6.63 (dd, 1H), 6.85 (t, 1H), 7.34-7.45 (m, 5H).

Example 3 Preparation of 2-(3-Methoxy-Phenyl)-4-Methoxy-Aceptophenone

Following the procedure described in E. Napolitano, et al., Gazz. Chim.Italia, 1988, 118, 101, a mixture of anisole (70 g, 0.64 mol),3-methoxyphenyl acetic acid (100 g, 0.6 mol), and 2 kg of PPA wasmechanically stirred at 75° C. for 75 minutes under an atmosphere ofnitrogen. The cooled, red reaction mixture was poured slowly intoice-water and then extracted with several portions of ethyl acetate. Thecombined extracts were washed with saturated sodium bicarbonate solutionand brine, dried over anhydrous sodium sulfate, filtered, and thesolvent removed in vacuo to give the crude product which was usedwithout further purification. The material may be purified by columnchromatography (Biotage) using hexanes-methylene chloride (2:1) aseluant. ¹H 500 MHz NMR(CDCl₃) ppm(δ): 3.81 (s, 3H), 3.89 (s, 3H), 4.23(s, 2H), 6.84 (dd, 1H), 6.88 (d, 1H), 6.89 (d, 1H), 6.95 (d, 2H), 7.26(t, 1H), and 8.02 (d, 2H).

Example 4 Preparation of 2-(3-Hydroxy-Phenyl)-4-Hydroxy-Acetophenone

A mixture of 2-(3-methoxyphenyl)-4-methoxy-acetophenone (148.4 g, 0.6mol), generated in Example 3, and pyridine-HCl (460 g, 3.98 mol) washeated to 184° C. under N₂ for 3.5 h. After this time, an additional 11g of pyridine hydrochloride was added and the mixture and heated furtherfor 1.8 h. Another 12.5 g of pyridine hydrochloride was added and afteranother 1.5 h, the reaction was cooled in an ice bath and ice/H₂O wasadded. The resulting mixture was extracted with EtOAc. The organicextract was washed with 2 N HCl and brine, dried over Na₂SO₄, andconcentrated in vacuo. The resulting brown residue was purified bysilica gel chromatography (Biotage) with 40% EtOAc/hexane as the eluantto afford the desired product as a yellow solid, and the mono-methoxyproduct which could be recycled; ¹H 500 MHz NMR(d₆-acetone) ppm(δ): 4.18(s, 2H), 6.69 (dd, 1H), 6.78 (m, 2H), 6.91 (d, 2H), 7.1 (t, 1H), and7.97 (d, 2H).

Example 5 Protecting Group Procedures for Phenyl-AcetophenoneDerivatives

Preparation of 4′-methoxymethyloxy-2-(4-triisopropylsilyloxy-phenyl)acetophenone (5a)Step A:

To a stirred solution of 3.0 g (13.2 mmol) of dry4,4′-dihydroxy-desoxybenzoin (prepared as described by Poirier, D.,etal, J. Med. Chem., 1994, 37, 1115; and freshly azeotroped withtoluene) in 25 mL of DMF at 0° C. was added 5.7 mL (5.7 mmol) of neatdiisopropylethylamine. To this stirred solution was added slowly 1.25 mL(19.73 mmol) of chloromethylmethylether (MOMCl). The ice-water bath wasremoved and the mixture was stirred further under an atmosphere ofnitrogen for 18 hours. The mixture was then poured into a saturatedNaHCO₃ solution, extracted with EtOAc, and the extract washed withwater, and dried over anhydrous MgSO₄. After evaporation of the solvent,the residue was purified by silica gel chromatography (EtOAc/Hexane=1:1)to provide the product, as a solid. ¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.0(d, 2H), 7.19(d, 2H), 7.10 (d, 2H), 6.8 (d, 2H), 5.23 (s, 2H), 4.8 (s,1H), 4.2 (s, 2H), 3.5 (s, 3H).

Step B:

To a stirred solution of the product obtained from Step A (423 mg, 1.55mmol) and imidazole (211 mg, 3.1 mmol) in 20 mL of dry DMF at 0° C. wasadded triisopropylsilyl chloride [TIPS-Cl] (3.1 mmol) and the reactionmixture was allowed to warm to room temperature and stirred further for2-3 hours. The reaction was quenched by the addition of aqueous NaHCO₃solution and extracted with EtOAc.

The organic layer was washed with brine and dried with MgSO₄.Chromatography (10% EtOAc/hexane) yielded the desired product. ¹H NMR(400 MH, CDCl₃) δ (ppm): 8.0 (d, 2H), 7.12 (d, 2H), 7.08 (d, 2H). 6.82(d, 2H), 5.21 (s, 2H), 4.18 (s, 2H), 3.5 (s, 3H), 1.24 (m, 3H), 1.1 (d,18H).

Utilizing one or both of the foregoing experimental steps the followingcompounds were prepared:

5b. 2-(3-hydroxy-phenyl)4-triisopropyloxy-acetophenone.

Using the ketone (8.7 g, 38 mmol) from Example 4 in anhydrous DMF (140mL) at 0° C. under N₂ was added Hunig's base (8.0 mL, 46 mmol) followedby dropwise addition of TIPS Cl (9.0 mL, 42 mmol). After stirring for 25min. at 0° C., the reaction was partitioned between ice/2N HCl andEtOAc. The organic layer was collected, washed with brine, dried overNa₂SO₄, filtered, and concentrated in vacuo to give an oil. The residuewas purified by silica gel chromatography with 20% EtOAc/hexane as theeluant to give the desired product as a yellow solid. ¹H 500 MHzNMR(CDCl₃) ppm(δ): 1.13 (d, 18H), 1.30 (m, 3H), 4.20 (s, 2H), 6.77-6.82(m, 3 H), 6.91 (d, 2H), 7.20 (t, 1 H), 7.99 (d, 2H).

5c. 4′-methox methyloxy-2-(3-triisopropylsilyloxy-phenyl)-acetophenone.

Using the material from Example 4 and final chromatography(hexanes-ethyl acetate, 85:15) gave the product. ¹H 500 MHz NMR(CDCl₃)ppm(δ): 1.07 (d, 18H), 1.2 (m, 3H), 3.5 (s, 3H), 4.19 (s, 2H), and 5.22(s, 2H).

5d. 2-(4-hydroxy-phenyl)-4-triisopropyloxy-acetophenone.

Utilizing the material from Example 4,2-(4-hydroxyphenyl)-1-{4-[(trisopropylsilyl)oxy]phenyl}ethanone wasprepared. ¹H NMR (500 MHz, CDCl3) 8 (ppm): 1.17 (d, 18H), 1.32 (m, 3H),4.20 (s, 2H), 6.80 (d, 2H), 6.94 (d, 2H), 7.18 (d, 2H), 7.99 (d, 2H).

5e. 2-(4-acetoxy-phenyl)-triisopropyloxy-acetophenone.

To a solution of 10.67 g (27.7 mmol) of ketone 5d, from Example 5, inmethylene chloride (150 mL) at 0° C. was added Hunig's base (6.3 mL,36.1 mmol), DMAP (1.01 g, 8.3 mmol), and acetyl chloride (2.4 mL, 33.3mmol) in that order under an atmosphere of nitrogen. After stirring for25 min., the reaction was partitioned between ethyl acetate and ice/2 NHCl. The organic layer was collected, washed with water and brine, anddried over sodium sulfate. Concentration in vacuo afforded the desiredprodcut as an orange solid. The solid was azeotroped with toluene andused without further purification. ¹H NMR (600 MHz, CDCl₃) δ (ppm): 1.10(d, 18H), 1.26 (m, 3H), 2.29 (s, 3H), 4.21 (s, 2H), 6.90 (d, 2H), 7.04(d, 2H), 7.27 (d, 2H), 7.98 (d, 2H).

Example 6 Bromination Procedure of Phenyl-Acetophenone Derivatives

Preparation of 4′-methoxymethyloxy- and 4′-hydroxy-2-bromo-2-(4-triisopropyloxy-phenyl)-acetophenones (6a,b)

To a stirred solution of 0.5 g (1.16 mmol) of the product from Step B ofExample 5 in 100 mL of anhydrous THF was added 0.39 g (1.16 mmol) oftrimethylphenylammonium perbromide (PTAB) at 0° C. The ice-water bathwas removed, and the mixture was stirred further for one hour. Thesolution was then filtered and washed with water and brine and driedover MgSO₄. Removal of the solvent afforded the mixture of bromo-ketones(the MOM group was partially removed), which was used without furtherpurification.

6a. Bromoketone With MOM Group:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 8.0 (d, 2H), 7.4 (d, 2H), 6.88 (d, 2H),6.86 (d, 2H), 6.36 (s, 1H), 1.24 (m, 3H), 1.1 (d, 18H);

6b. Bromoketone Without MOM Group:

¹H NMR (400 MHz, CDCl₃) δ (ppm): 7.94 (d, 2H), 7.4 (d, 2H), 6.88 (d,2H), 6.86 (d, 2H), 6.36 (s, 1H), 1.24 (m, 3H), 1.1 (d, 18H).

Alternatively, after the mixture was stirred for one hour, a few dropsof 48% HBr was added to the mixture and it was stirred further until athin layer chromatogram indicated that the removal of the methoxymethyl(MOM) group was complete, thus yielding only4′-hydroxy-2-bromo-2-(4-triisopropylsilyloxy-phenyl)-acetophenone 6b.

6c. Preparation of4′-hydroxy-2-(3-triisopropylsilyloxy-phenyl)-acetophenone.

To a stirred solution of 40.7 g (0.095 mol) of4′-methoxymethyloxy-2-(3-triisopropylsilyloxy-phenyl)-acetophenone (5c),from Example 5, in 400 mL of dichloromethane at 0° C. was added all atonce 37.5 g (0.099 mol) of solid trimethylammoniumphenyl perbromide. Theice-water bath was removed and the reaction mixture was stirred furtherfor 4 h under an inert atmosphere of nitrogen. The reaction mixture waspartitioned between ethyl acetate, ice, brine, 5% aqueous sodiumthiosulfate, and saturated sodium bicarbonate. The organic phase wasseparated washed with brine; dried over anhydrous sodium sulfate,filtered, evaporated, and dried in vacuo to give the crude product whichwas used without further purification. ¹H 500 MHz NMR(CDCl₃) ppm(δ):1.07 (d, 18H), 1.2 (m, 3H), and 6.3 (s, 1H).

Using the foregoing procedures the following compound was prepared:

6d. 4-triisopropylsilyloxy-2-bromo-2-(3-hydroxyphenyl)-acetophenone.

Using 8.93 g (23 mmol) of4-triisopropylsilyloxy-2-(3-hydroxyphenyl)-acetophenone (5b) fromExample 5, crude4-triisopropylsilyloxy-2-bromo-2-(3-hydroxyphenyl)-acetophenone wasrealized which was used without further purification. ¹H 500 MHzNMR(CDCl3) ppm(δ): 1.10 (d, 18H), 1.25 (m, 3H), 6.29 (s, 1H), 6.80-7.22(m, 6 H), 7.90 (d, 2H);

6e. 4-triisopropylsilyloxy-2-bromo-2-(3-acetoxyphenyl)-acetophenone.

Using the ketone 5e, prepared in Example 5, the desired product wasobtained as an orange oil and was used without further purification. ¹HNMR (500 MHz, CDCl₃) δ (ppm): 1.10 (d, 18H), 1.28 (m, 3H), 2.29 (s, 3H),6.35 (s, 1H), 6.90 (d, 2H), 7.12 (d, 2H), 7.59 (d, 2H), 7.98 (d, 2H).

6f. 4-iodo-2-bromo-2-(3-benzyloxyphenyl)-acetophenone.

Utilizing the ketone (1.82 g, 4.2 mmol), prepared by the reaction of3-benzyloxybenzylmagnesium chloride and Weinreb amide of p-iodobenzoicacid, the desired product was obtained as a colorless oil and was usedwithout further purification. ¹H 500 MHz NMR(CDCl₃) ppm(δ): 5.09 (s,21), 6.25 (s, 1H), 6.99 (dd, 1H), 7.23-7.36 (m, 2H), 7.30-7.43 (m, 6H),7.69 (d, 2H), 7.81 (d, 2H).

Example 7 Preparation of Thioketones

Preparation of2-(2-hydroxy-5-benzyloxyphenylthio)-2-(3-triisopropylsilyloxy-phenyl)4-hydroxy-acetophenone(7a).

To a stirred solution of a mixture of 23.2 g (0.099 mole) of2-hydroxy-5-benzyloxythiophenol and 13.5 g (0.1 mole) ofdiisopropylethylamine in 50 mL of sieve dried DMF at 0° C. under aninert atmosphere of nitrogen was added dropwise a solution of ˜0.095mole of crude2-bromo-2-(3-hydroxy-phenyl)4-methoxymethyloxy-acetophenone (6c), fromExample 6, in 150 mL of sieve dried DMF over 15 minutes. The resultingreaction mixture was stirred further for 3 h and then partitionedbetween 2N HCl/ice/water and ethyl acetate. The ethyl acetate extractwas washed thrice with water and finally with brine; dried overanhydrous sodium sulfate, filtered, evaporated, and dried in vacuo togive the crude product, which was used without further purification.

-   ¹H 500 MHz NMR(CDCl₃) ppm(δ): 1.07 (d, 18H), 1.2 (m, 3H), 4.84 (s,    2H), and 5.6 (s, 1H).

Utilizing the above procedure the following compounds were prepared:

7b.2-(2-hydroxy-5-benzyloxyphenylthio)-2-(4-triisopropylsilyloxy-phenyl)4hydroxy-acetophenone.

Using the bromoketone 6b from Example 6 and the mercaptan from Example1, the desired product was obtained after silica gel chromatographyusing EtOAc/hexane (1:5) as the eluant. ¹H NMR (500 MHz, acetone-d₆) δ(ppm): 7.95 (d, 2H), 7.40 (m, 5H), 7.20 (d, 2H), 6.80 (m, 7H), 6.20 (s,1H), 4.85 (s, 2H), 1.23 (m, 3H), 1.10 (m, 18H); MS m/z 616 (W⁺+1).

7c.2-(2,5-dihydroxy-6-fluoro-phenylthio)-2-(3-hydroxy-phenyl)4-triisopropylsilyloxy-acetophenone.

Using a solution of the crude thiol (13.31 g, 83 mmol) from Example 2and the crude bromoketone 6d (64 mmol) prepared in Example 6, thedesired product was obtained as a yellow foam after silica gelchromatography with 30% EtOAc/hexane as the eluant.

-   ¹H 500 MHz NMR(CDCl₃) ppm(δ): 1.09 (d, 18H), 1.28 (m, 3H), 4.65 (bd,    1H), 4.91 (bs, 1 H), 5.78 (s, 1H), 6.67-7.17 (m, 8H), 7.69 (s, 1H),    7.82 (d, 2H).    7d.    2-(2,5-dihydroxy-6-fluoro-phenylthio)-2-(3-acetoxy-phenyl)4-triisopropylsilyloxy-acetophenone.

Using a solution of the crude thiol from Example 2 and the crudebromoketone 6e, prepared in Example 6, the desired coupled product wasobtained. ¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.08 (d, 18H), 1.27 (m, 3H),2.28 (s, 3H), 5.83 (s, 1H), 6.68 (d, 1H), 6.80 (d, 2H), 6.93 (t, 1H),6.94 (d, 2H), 7.15 (d, 2H), 7.82 (d, 2H).

7e.2-(2-hydroxy-5-benzyloxy-6-fluoro-phenylthio)-2-(3-acetoxy-phenyl)4-triisopropylsilyloxy-acetophenone.

Using a solution of the crude thiol from Example 2 and the crudebromoketone 6f, prepared in Example 6, the desired coupled product wasobtained after silica gel chromatography with 15% ethyl acetate/hexaneas the eluant. ¹H NMR (500 MHz, CDCl₃) δ (ppm): 4.95-4.99 (m, 4H), 5.76(s, 1H), 6.63 (dd, 1H), 6.79-6.88 (m, 3H), 6.94 (t, 1H), 7.19 (t, 1H),7.32-7.41 (m, 10H), 7.54 (d, 2H), 7.71 (d, 2H).

Example 8 General Procedure for the Formation of Dihydro-Benzoxathiins

Preparation of(+)-4-((2S,3R)-6-(benzyloxy)-3-{3-[(triisopropylsilyl)oxy]phenyl}-2,3-dihydro-1,4-benzoxathiin-2-yl)phenol(8a)

To a stirred solution of ˜97 mmol of crude2-(2-hydroxy-5-benzyloxyphenylthio)-2-(3-tri-isopropylsilyloxyphenyl)4-hydroxy-acetophenone(7a), prepared in Example 7, in 400 mL of dichloromethane at 0° C. wasadded 111 g (970 mmol) of neat trifluoroacetic acid (TFA) under an inertatmosphere of nitrogen. To this stirred mixture at 0° C. was addeddropwise 34 g (291 mmol) of neat triethylsilane (TES) and after stirringfor ˜2 hour an additional 20 mL of TES was added to drive the reactionto completion. The mixture was then stirred further for 2 h. Thereaction was confirmed to be complete by working up an aliquot andexamining the proton NMR of the residue. The reaction mixture waspartitioned between ethyl acetate/brine/ice/saturated sodium bicarbonatesolution and the organic phase was separated, washed again withsaturated sodium bicarbonate and finally with brine, dried overanhydrous sodium sulfate, filtered, and evaporated.

Purification by silica gel chromatography (Biotage) using hexanes-ethylacetate (85:15) gave the product as a yellow oil;

-   ¹H 500 MHz NMR(CDCl₃) ppm(δ): 1.07 (d, 18H), 1.2 (m, 3H), 4.29 (d,    1H), 5.05 (s, 2H), and 5.49 (d, 1H).

The positively rotating enantiomer was obtained via chiralchromatography on a Chiralpak® AD™ 4.6×250 mm column, available fromDaicel Chemical Industries, Ltd., using heptane-isopropanol (85:15) aseluant @ 1 ml/min; retention time=5.2 min; [α]_(D)=+240.5° (c=1.045,MeOH).

Utilizing the above procedure the following compounds were prepared:

8b.4-((2S,3R)-6-(benzyloxy)-3-{4-[(triisopropylsilyl)oxy]phenyl}-2,3-dihydro-1,4-benzoxathiin-2-yl)phenol.

Using the thioketone 7b, from Example 7, the desired product wasobtained after purification by silica gel chromatography using 5%EtOAc/hexane as the eluant. ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.5-7.3 (m,5H), 6.94 (d, 1H), 6.85 (d, 2H), 6.80 (d, 2H), 6.74 (dd, 2H), 6.65(m,4H), 5.43 (d, J=2.1 Hz, 1H), 5.05 (d, 2H), 4.30 (d, J=2.1 Hz, 1H), 1.23(m, 3H), 1.10 (d, 18H).

Each enantiomer of the racemic dihydrobenzoxathiin was obtained viachiral chromatography using a Chiralpak® AD™ column, available fromDaicel Chemical Industries, Ltd., with 30% isopropanol in hexane as theeluant; the desired fast moving isomer: [α]_(D)=+184.4° (c=0.725, MeOH);and the slow moving isomer: [α]_(D)=−188.5° (c=0.74, MeOH).

8c.5-fluoro-3-(3-hydroxyphenyl)-2-{4-[triisopropylsilyl)oxy]phenyl}-2,3-dihydro-1,4-benzoxathiin-6-ol.

Using the thioketone 7c, from Example 7, the expected diol was realizedas an off-white foam, after purification by silica gel chromatographywith 30% EtOAc/hexane as the eluant.

-   ¹H 500 MHz NMR(CDCl₃) ppm(δ): 1.11 (d, 18H), 1.25 (m, 3H), 4.33 (d,    J=2.3 Hz, 1H), 5.42 (d, J=2.1 Hz, 1H), 6.38-6.97 (m, 10 H).    8d.    5-fluoro-6-(benzyloxy)-3-[3-(benzyloxy)phenyl]-2-(4-iodophenyl)-2,3-dihydro-1,4-benzoxathiine.

Starting with the adduct 7e (2.00 g, 3.0 mmol), prepared in Example 7,and slightly modifying the procedure, the crude product was isolatedafter stirring at 0° C. to ambient temperature for 5 h and storage at 0°C. for 15 h. Purification by silica gel chromatography with 15% ethylacetate/hexane as the eluant afforded the desired product as a whitesticky gum. 1H NMR (500 MHz, CDCl₃) δ (ppm): 4.37 (d, J=2.3 Hz, 1H),4.86 (m, 2H), 5.16 (s, 2H), 5.41 (d, J=2.0, 1H), 6.48-6.52 (m, 2H),6.71-6.84 (m, 5H), 7.05 (t, 1H), 7.35-7.43 (m, 10H), 7.57 (d, 2H).

8e.4-(5-fluoro-6-hydroxy-2-{4-[(triisopropylsilyl)oxy]phenyl}-2,3-dihydro-1,4-benzoxathiin-3-yl)phenylacetate.

Utilizing the thioketone 7d, prepared in Example 7, the desired productwas obtained.

-   ¹H NMR (500 MHz, CDCl₃) δ (ppm): 0.98 (d, 18H), 1.27 (m, 3H), 2.26    (s, 3H), 4.37 (d, J=2.1 Hz, 1H), 5.41 (d, J=2.1 Hz, 1H), 6.73-6.86    (m, 10H).    8f.    5-fluoro-3-(4hydroxyphenyl)-2-{4-[(triisopropylsilyl)oxy]phenyl}-2,3-dihydro-1,4-benzoxathiin-6-ol.

To a solution of 8e (100.36 g, 187 mmol) in anhydrous TBF (1 liter), at0° C. under nitrogen was added a 1 M solution of lithiumtriethylborohydride in TBF (561 mL) via a dropping funnel over 45 min.After stirring for 5 min., an additional 160 mL of super-hydride wasadded to the reaction in 20 mL increments until the starting materialwas consumed as monitored by TLC (15% ethyl acetate/hexane). After atotal of 1 hour 15 min., the reaction was quenched with cold 2 N HCl.The mixture was extracted with ethyl acetate. The organic layer wascollected, washed with brine, dried over sodium sulfate, andconcentrated in vacuo. Purification by silica gel chromatography with15% ethyl acetate/hexane as the eluant afforded the desired product as ayellow foam. ¹H NMR (500 MHz, CDCl₃) δ (ppm): 1.10 (d, 18H), 1.27 (m,3H), 4.34 (d, J=2.1 Hz, 1H), 5.41 (d, J=2.0 Hz, 1H), 6.59 (d, 2H), 6.75(m, 6H), 6.85 (d, 2H).

8 g.4-(5-fluoro-6-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-2-yl}phenox)(triisopropyl)silane.

Utilizing the procedure outlined in Example 9, Step A, compound 8f wasconverted to the desired product, a tan solid. The crude material wasazeotroped with toluene and used without further purification. ¹H NMR(500 MHz, CDCl₃) δ (ppm): 1.10 (d, 18H), 1.27 (m, 3H), 3.44 (s, 3H),3.58 (s, 3H), 4.34 (d, J=2.1 Hz, 1H), 5.11 (s, 21), 5.19 (s, 2H), 5.43(d, J=2.1 Hz, 1H), 6.74-6.79 (m, 7H), 6.86 (d, 2H), 6.94 (t, 1H).

8h.4-(5-fluoro-6-(methoxymethoxy)-3-[4-(methoxymethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-2-ylphenol.

Utilizing the procedure outlined in Example 9, Step B, compound 8 g wasconverted to the desired product 8h. ¹H NMR (500 MHz, CDCl₃) δ (ppm):3.46 (s, 3H), 3.59 (s, 3H), 4.37 (d, J=2.3 Hz, 1H), 5.13 (s, 2), 5.20(s, 2H), 5.43 (d, J=1.8 Hz, 1H), 6.68-6.96 (m, 10H).

8i.6-(benzyloxy)-3-[3-(benzyloxy)phenyl]-2-(4-iodophenyl)-2,3-dihydro-1,4-benzoxathiine.

Utilizing the requisite thioketone, prepared as described in Example 7,the desired product was obtained. ¹H NMR (500 MH, CDCl₃) δ (ppm): 7.58(d, 2H), 7.5-7.3 (m),7.05 (t, 1), 6.94 (d, 11), 6.84 (d, 1H), 6.82-6.4(m), 6.56 (t, 1H), 6.52 (d, 1H), 5.44 (d, 1H), 5.06 (s, 2H), 4.86 (q,2H), 4.34 (d, 1H).

Example 9 Chiral Preparation of

Preparation of(+)-4-{(2S,3R)-5-fluoro-6-(methoxymethoxy)-3-[3-(methoxymethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-2-yl}phenol.Step A:

To a solution of the product 8c, obtained from Example 8, (5.38 g, 10mmol) in distilled THF (60 mL) at 0° C. under N₂ was added MOMCl (1.9mL, 26 mmol) followed by portion-wise addition of 95% NaH (0.6164 g, 22mmol). The reaction became dark green but with time became yellow/brown.After stirring for 1 h, the reaction appeared mostly complete by TLC(30% EtOAc/hexane). Additional MOMCl (1 mL) was added to drive thereaction to completion. After 15 min., the reaction was partitionedbetween EtOAc and ice/water. The organic layer was collected, washedwith brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. Thecrude residue was used without further purification. ¹H 500 MHzNMR(CDCl3) ppm(δ): 1.10 (d, 18H), 1.25 (m, 3H), 3.39 (s, 3H), 3.58 (s,3H), 4.36 (d, J=2.1 Hz, 1H), 5.00 (m, 2 H), 5.19 (s, 2H), 5.43 (d, J=1.9Hz, 1 H), 6.57-7.03 (m, 10H).

Step B:

To a solution of the isolate from Step A (10 mmol) in distilled THF (60mL) was added AcOH (0.76 mL, 13 mmol) at 0° C. under N₂ followed by a 1M solution of TBAF in THF (11 mL, 11 mmol). After 5 min., the reactionwas complete and the reaction was partitioned between saturated NaHCO₃and EtOAc. The organic layer was collected, washed with brine, driedover Na₂SO₄, filtered, and concentrated in vacuo. The crude material waspurified by silica gel chromatography with 40% EtOAc/hexane as theeluant to afford the desired product as a light yellow solid. ¹H 500 MHzNMR(CDCl3) ppm(δ): 3.39 (s, 3H), 3.59 (s, 3H), 4.37 (d, J=2.3 Hz ,1H),4.99 (s, 2 H), 5.20 (s, 2H), 5.44 (d, J=2.1 Hz, 1 H), 6.55-7.08 (m,10H).

The racemic benzoxathiin was resolved via chiral chromatography on aChiralcel® OD™ column (150 mm diameter), available from Daicel ChemicalIndustries, Ltd., using 20% iPrOH in heptane as the eluant (400 mL/min).The faster moving isomer was identified as the (+) enantiomer by aPDR-Chiral laser polarimeter.

Example 9A Chiral Preparation of

The racemic benzoxathiin 8h, from Example 8, was resolved via chiralchromatography on a Chiralpak AD 100×250 mm column, usingisooctane:isopropanol 50:50 as the eluant (300 mL/min) and ˜2.5 gracemate per injection with monitoring at 310 nM. The (+) enantiomereluted at 8.8 min, and the (−) enantiomer eluted at 13.5 min.

The Analytical Conditions: Chiralcel AD 4.6×250 mm column,heptane:isopropanol 80:20, at 1 mL/min, at 220 nM. The (−) enantiomereluted at 8.1 min, and the (+) enantiomer eluted at 9.7 min.

Example 10 Preparation of Dihydro-Benzoxathiin Derivatives

Preparation of1-{(1S)-2-[4-((2S,3R)-6-(benzyloxy)-3-{4-[(triisopropylsilyl)oxy]phenyl}-2,3-dihydro-1,4-benzoxathiin-2-yl)phenoxy]-1-methylethyl}pyrolidine(10a).Step A:

To a stirred solution of a mixture of 242.6 mg (0.4 mmol) of(+)-4-((2S,3R)-6-(benzyloxy)-3-{3-[(triisopropylsilyl)oxy]phenyl}-2,3-dihydro-1,4-benzoxathiin-2-yl)phenol(8b), obtained from Example 8, triphenylphosphine (319 mg, 1.2 mmol),and (S)-2-pyrrolidino-1-propanol (157 mg, 1.2 mmol) in 4 mL of anhydrousTBF at ambient temperature was added dropwise 239 μL (1.2 mmol) ofdiisopropyl azodicarboxylate (DIAD). The resulting solution was stirredfurther for 18.5 hours. The mixture was partitioned between ethylacetate/2N HCl. The organic phase was separated and washed with amixture of brine and saturated sodium bicarbonate, and again with brine;dried over anhydrous sodium sulfate; filtered, and evaporated. Theresidue was purified by plate layer silica gel chromatography (PLC)using ethyl acetate as the eluant to give the normal product (NMR givenin table below), and the rearranged product. ¹H NMR (500 MHz, CDCl₃) δ(ppm): 7.5-7.34 (m, 5H), 6.9-6.7 (m, 10H), 6.26 (d, 1H), 5.46 (d, 1H),5.01 (s, 2H), 4.26 (d, 1H), 4.05 (t, 2H), 2.87 (t, 2H), 2.6 (m, 4H), 1.8(m, 4H), 1.22 (m, 3H), 0.97 (d, 18H).

Utilizing the foregoing procedure and the appropriate chiralpyrrolidine-ethanol derivative the following compounds were prepared:

OTIPS Spectroscopic Data R² R³ position (¹H 500 MHz NMR, δ, ppm,CDCl₃/Mass Spec.) H H 4 1.08 (d, 21H), 1.23 (m, 3H), 1.8 (m, 4H), 2.69(m, 5H), 3.8 (m, 1H), 4.05 (m, 1H), 4.3 (d, J = 2 Hz, 1H), 5.04 (s, 2H),5.42 (d, J = 2 Hz, 1H), 6.64-6.92 (m, 11H), 7.35-7.47 (m, 5H) H H 3 0.99(d, 21H), 1.03 (m, 3H), 1.8 (m, 4H), 2.7 (m, 5H), 3.86 (m, 1H), 4.06 (m,1H), 4.3 (d, J = 2 Hz, 1H), 5.05 (s, 2H), 5.49 (d, J = 2 Hz, 1H), 6.34(d, J = 7.6 Hz, 1H), 6.7-6.98 (m, 10H), 7.36-7.48 (m, 5H) β-CH₃ H 4 1.09(d, 21H), 1.24 (m, 4H), 2.0-3.1 (m's, 7H), 3.8 (m, 1H), 4.05 (m, 1H),4.3 (d, J = 2 Hz, 1H), 5.05 (s, 2H), 5.42 (d, J = 2 Hz, 1H), 6.66-6.93(m, 11H), 7.36- 7.48 (m, 5H) β-CH₃ α-CH₃ 4 1.01 (d, 6H), 1.07 (d, 18H),1.20 (d, 3H), 1.20 (m, 3H), 1.70 (m, 2H), 2.41 (m, 2H), 2.76-2.95 (m,3H), 3.80 (m, 1H), 4.02 (m, 1H), 4.29 (d, J = 2.2 Hz, 1H), 5.01 (s, 2H),5.40 (d, J = 2.1 Hz, 1H), 6.63-6.90 (m, 11H), 7.33-7.50 (m, 5H) α-CH₃β-CH₃ 4 1.02 (d, 6H), 1.07 (d, 18H), 1.20 (d, 3H), 1.22 (m, 3H), 1.72(m, 2H), 2.42 (m, 2H), 2.75-2.97 (m, 3H), 3.75 (m, 1H), 4.02 (m, 1H),4.29 (d, J = 2.0 Hz, 1H), 5.03 (s, 2H), 5.40 (d, J = 1.8 Hz, 1H),6.64-6.91 (m, 11H), 7.34-7.45 (m, 5H) β-CH₃ β-CH₃ 4 0.94 (2 d's, 6H),1.07 (d, 18H), 1.23 (d, 3H), 1.23 (m, 3H), 2.10 (m, 2H), 2.29 (m, 2H),2.72 (m, 1H), 3.20 (m, 2H), 3.79 (m, 1H), 4.02 (m, 1H), 4.29 (d, J = 2.2Hz, 1H), 5.03 (s, 2H), 5.41 (d, J = 2.0 Hz, 1H), 6.64-6.91 (m, 11H),7.34-7.45 (m, 5H) β-CH₃ α-CH₃ 3 0.99-1.04 (m, 27H), 1.6-3.0 (m, 7H), 3.8(m, 1H), 4.07 (m, 1H), 4.29 (d, 1H), 5.04 (s, 2H), 5.48 (d, 1H), 6.32(d, 1 = 7.6 Hz, 1H), 6.7-6.96 (m, 10H), 7.35- 7.48 (m, 5H) β-CH₃ H 30.98 (d, 18H), 1.01 (d, 3H), 1.01 (m, 3H), 1.21 (d, 3H), 1.36 (m, 1H),2.02 (m, 1H), 2.15 (m, 1H), 2.23 (m, 1H), 2.60 (m, 1H), 2.75 (m, 1H),2.91 (m, 1H), 3.03 (m, 1H), 3.81 (m, 1H), 4.02 (m, 2H), 4.28 (d, J = 2.2Hz, 1H), 5.03 (s, 2H), 5.43 (d, J = 2.0 Hz, 1H), 6.31 (d, 1H), 6.66-6.97(m, 11H), 7.34-7.45 m, 5H) α-CH₃ H 3 1.09 (d, 21H), 1.25 (m, 3H),2.0-3.1 (m's, 7H), 3.8 (m, 1H), 4.05 (m, 1H), 4.31 (d, J = 2 Hz, 1H),5.05 (s, 2H), 5.43 (d, J = 2 Hz, 1H), 6.65-6.93 (m, 11H), 7.36- 7.48 (m,5H)Step A:

Utilizing the foregoing procedure with the chiral material prepared inExample 9 and the appropriate chiral pyrrolidine-ethanol derivative thefollowing compounds were prepared:

OMOM Spectroscopic Data R² R³ position (¹H 500/600 MHz NMR, δ, ppm,CDCl₃/Mass Spec.) β-CH₃ H 4 1.05 (d, 3H), 1.27 (d, 3H), 1.40 (m, 1H),2.03- 2.31 (m, 3H), 2.65 (m, 1H), 2.80 (m, 1H), 2.94 (m, 1H), 3.09 (m,1H), 3.45 (s, 3H), 3.57 (s, 3H), 3.87 (m, 1H), 4.08 (m, 1H), 4.36 (d, J= 1.9 Hz, 1H), 5.12 (m, 2H), 5.17 (s, 2H), 5.42 (d, J = 1.6 Hz, 1H),6.73-6.94 (m, 10H). α-CH₃ β-CH₃ 3 1.03 (d, 6H), 1.74 (m, 2H), 2.39 (m,2H), 2.83- 2.92 (m, 4H), 3.37 (s, 3H), 3.57 (s, 3H), 4.03 (m, 2H), 4.37(d, J = 2.2 Hz, 1H), 4.97 (s, 2H), 5.18 (s, 2H), 5.43 (d, J = 2.1 Hz,1H), 6.55-7.07 (m, 10H) H H 3 1.22 (d, 3H), 1.81 (m, 4H), 2.68 (m, 5H),3.39 (s, 3H), 3.59 (s, 3H), 3.83 (m, 1H), 4.02 (m, 1H), 4.37 (d, J = 1.9Hz, 1H), 4.96 (s, 2H), 5.17 (s, 2H), 5.43 (d, J = 1.8 Hz, 1H), 6.54-7.08(m, 10H) β-CH₃ β-CH₃ 3 0.90 (2 d's, 6H), 1.21 (d, 3H), 2.12 (m, 2H),2.29 (m, 2H), 2.73 (m, 1H), 3.20 (m, 2H), 3.39 (s, 3H), 3.59 (s, 3H),3.80 (m, 1H), 4.02 (m, 1H), 4.39 (d, J = 2.3 Hz, 1H), 4.98 (s, 2H), 5.19(s, 2H), 5.42 (d, J = 2.3 Hz, 1H), 6.54-7.08 (m, 10H) β-CH₃ H 3 1.01 (d,3H), 1.21 (d, 3H), 1.36 (m, 1H), 2.02 (m, 1H), 2.10 (t, 1H), 2.23 (m,1H), 2.58 (m, 1H), 2.70 (m, 1H), 2.87 (m, 1H), 3.00 (t, 1H), 3.39 (s,3H), 3.59 (s, 3H), 3.81 (m, 1H), 4.02 (m, 1H), 4.38 (d, J = 2.3 Hz, 1H),4.96 (s, 2H), 5.17 (s, 2H), 5.43 (d, J = 2.3 Hz, 1H), 6.54-7.08 (m, 10H)

Example 10A Preparation of

A flask equipped with a reflux condenser was charged with theiodobenzoxathiin 8d (0.0446 g, 0.068 mmol), obtained from Example 8,followed by copper iodide (0.0017 g, 0.0068 mmol), 2,2′-dipydidyl(0.0016 g, 0.0082 mmol), and potassium carbonate (0.0284 g, 0.20 mmol).Xylene (0.5 mL) was then added to the flask followed by(2S)-2-[(3R)-3-methylpyrrolidin-1-yl]propan-1-ol (0.048 g, 0.34 mmol).The reaction was degassed and heated to 140° C. under nitrogen for 21 h.The reaction was diluted with toluene and filtered through celite. Thefiltrate was partitioned between ethyl acetate and ice/2 N HCl. Theorganic layer was collected, washed with saturated sodium bicarbonateand brine, dried over sodium sulfate, and concentrated in vacuo to givea brown oil. The crude material was purified by silica gelchromatography with 10% methanol/methylene chloride as the eluant togive the desired product as an orange foam.

Example 10B Preparation of

Similarly, following the procedure described in Example 10A andutilizing the iodobenzoxathiin derivative 8i, from Example 8, the abovecompound was obtained.

-   ¹H NMR (500 MHz, CDCl₃) δ (ppm): 7.5-7.3 (m), 7.04 (t, 1H), 6.94    (dd, 2H), 6.83 (d, 1H), 6.79 (d, 2H), 6.74 (dd, 1H), 6.62 (brt, 1H),    6.56 (d, 1H), 5.48 (d, 1H), 5.06 (s, 2H), 4.86 (q, 2H), 4.34 (d,    1H), 4.04 (dd, 1H), 3.82 (dd, 1H), 3.0 (t, 1H), 2.9 (m, 1H), 2.7 (m,    1H), 2.55 (m, 1H), 2.3 (m, 1H), 2.1 (t, 1H), 2.02 (m, 1H), 1.35 (m,    1H), 1.22 (d, 3H), 1.05 (d, 3H).;

Example 11 Preparation of Dihydro-Benzoxathiins

Preparation of(2S,3R)-3-(4hydroxyphenyl)-2-(4-{[(2S)-2-pyrrolidin-1-ylpropyl]oxy}phenyl)-2,3-dihydro-1,4-benzoxathiin-6-ol(11a).Step A:

A stirred mixture of 102 mg (0.14 mmol) of compound 10a, generated inExample 10, Step A, 30.6 mg (0.29 mmol) of palladium black and 181.2 mg(0.29 mmol) ammonium formate in 3 mL of EtOH/EtOAc/H₂O (7:2:1) washeated at 80° C. for 2 h. The reaction mixture was filtered through apad of Celite® to remove the catalyst, washed thoroughly withEtOH/EtOAc/H₂O (7:2:1), and the filtrate was partitioned between waterand EtOAc. The organic phase was separated, dried over Na₂SO₄, filtered,evaporated, and dried in vacuo to give the crude product which was usedwithout purification.

Step B:

To a stirred solution of a mixture of the debenzylated product (87.2 mg,0.14 mmol), generated in Step B, and 49.2 μL (0.84 mmol) of HOAc in 2 mLof TEF was added 281 μL (0.28 mmol) a IM solution of tetrabutylammoniumfluoride in THF at room temperature. The resulting solution was allowedto stir for three hours at room temperature. The mixture was partitionedbetween EtOAc, saturated aqueous NaHCO₃ and brine and the organic layerwas separated, washed with brine, dried over Na₂SO₄, filtered, andevaporated. Purification by plate layer silica gel chromatography usingEtOAC-MeOH (9:1) as the eluant afforded the desired product (NMR givenin the table below).

Step C:

Using the MOM-protected-fluorine containing adducts, from Step A′ inExample 10, a MeOH solution was treated with 2 N HCl and heated to 80°C. under N₂ for 45 min. The reaction was partitioned between EtOAc andice/saturated NaHCO₃. The organic layer was collected, washed withbrine, dried over Na₂SO₄, filtered, and evaporated. Purification byplate layer silica gel chromatography using either methylenechloride/methanol (9:1) or methylene chloride/ethyl acetate (9:1) as theeluants gave the following compounds listed in the table.

Utilizing the foregoing procedures the following compounds wereprepared:

Spectroscopic Data (¹H 500 MHz NMR, δ, ppm, d₆- R¹ R² R³ R⁴ R⁸ R⁷position acetone/Mass Spec./[α]) H H H α-CH₃ β-CH₃ H 3 1.05 (2d, 6H),1.33 (m, 1H), 1.65- 1.70 (m, 2H), 1.86 (m, 1H), 2.64 (m, 1H), 2.82-2.84(m, 2H), 3.26 (m, 1H), 3.84 (m, 1H), 4.02 (m, 1H), 4.54 (d, J = 2.3Hz,1H), 5.46 (d, J = 2.3 Hz, 1H), 6.42 (d, 1H), 6.59-6.66 (m, 4H), 6.81 (d,2H), 6.83 (d, 1H), 6.92 (t, 1H), 7.08 (d, 2H); MS m/z 478.1 (M⁺ + 1). HH H α-CH₃ α-CH₃ H 3 1.03 (d, 3H), 1.19 (d, 3H), 1.33 (m, 1H), 1.63-1.72(m, 2H), 1.84 (m, 1H), 2.64 (m, 1H), 2.96 (m, 1H), 3.06 (m, 1H), 3.26(m, 1H), 3.84 (m, 1H), 4.10 (m, 1H), 4.54 (d, J = 2.3 Hz, 1H), 5.46 (d,J = 2.2 Hz, 1H), 6.42 (d, 1H), 6.59-6.66 (m, 4H), 6.81 (d, 2H), 6.83 (d,1H), 6.92 (t, 1H), 7.08 (d, 2H); MS m/z 478.1 (M⁺ + 1). H H H β-CH₃α-CH₃ H 3 1.05 (2d, 6H), 1.33 (m, 1H), 1.65-1.70 (m, 2H), 1.86 (m, 1H),2.64 (m, 1H), 2.82-2.84 (m, 2H), 3.26 (m, 1H), 3.84 (m, 1H), 4.02 (m,1H), 4.54 (d, J = 2.3 Hz, 1H), 5.46 (d, J = 2.3 Hz, 1H), 6.42 (d, 1H),6.59-6.66 (m, 4H), 6.81 (d, 2H), 6.83 (d, 1H), 6.92 (t, 1H), 7.08 (d,2H); MS m/z 478.1 (M⁺ + 1). H H H β-CH₃ β-CH₃ H 3 1.03 (d, 3H), 1.19 (d,3H), 1.33 (m, 1H), 1.63-1.72 (m, 2H), 1.84 (m, 1H), 2.64 (m, 1H), 2.96(m, 1H), 3.06 (m, 1H), 3.26 (m, 1H), 3.84 (m, 1H), 4.10 (m, 1H), 4.54(d, J = 2.3 Hz, 1H), 5.46 (d, J = 2.2 Hz, 1H), 6.42 (d, 1H), 6.59-6.66(m, 4H), 6.81 (d, 2H), 6.83 (d, 1H), 6.92 (t, 1H), 7.08 (d, 2H); MS m/z478.1 (M⁺ + 1). F β-CH₃ H H H α-CH₃ 3 0.98 (d, 3H), 1.21 (d, 3H), 1.22(m, 1H), 1.93 (m, 1H), 2.15 (m, 2H), 2.53-2.80 (m, 5H), 4.52 (m, 1H),4.61 (d, J = 2.3 Hz, 1H), 5.46 (d, J = 2.0 Hz, 1H), 6.41 (d, 1H),6.59-6.81 (m, 6H), 6.91 (t, 1H), 7.07 (d, 2H); MS mlz 496.1 (M⁺ + 1) Fα-CH₃ H α-CH₃ H H 3 0.98 (d, 3H), 1.14 (d, 3H), 1.25 (m, 1H), 1.93 (m,1H), 2.16 (m, 2H), 2.64-2.90 (m, 4H), 3.77 (m, 1H), 4.05 (m, 1H), 4.60(d, J = 2.3 Hz, 1H), 5.45 (d, J = 2.2 Hz, 1H), 6.41 (d, 1H), 6.59-6.81(m, 6H), 6.91 (t, 1H), 7.07 (d, 2H); MS m/z 496.4 (M⁺ + 1) F β-CH₃ Hβ-CH₃ H H 4 0.99 (d, 3H), 1.17 (d, 3H), 1.27 (m, 1H), 1.97 (m, 1H), 2.18(m, 2H), 2.63-2.90 (m, 4H), 3.79 (m, 1H), 4.07 (m, 1H), 4.60 (d, J = 2.0Hz, 1H), 5.46 (d, J = 2.1 Hz, 1H), 6.60 (d, 2H), 6.71-6.83 (m, 8H), 7.05(d, 2H), MS m/z 496.1 (M⁺ + 1) H H H β-CH₃ H H 4 1.18 (d, J = 6.6 Hz,3H), 1.8 (m, 4H), 2.62 (m, 4H), 2.7 (m, 1H), 3.8 (m, 1H), 4.08 (m, 1H),4.53 (d, J = 2 Hz, 1H), 5.44 (d, J = 2 Hz, 1H), 6.58 (m, 2H), 6.59 (d, J= 8.5 Hz, 2H), 6.6 (d, J = 3 Hz, 1H), 6.8 (d, J = 8.7 Hz, 2H), 6.83 (d,J = 8.5 Hz, 2H), 7.05 (d, J = 8.7 Hz, 2H) H H H β-CH₃ H H 3 1.18 (d, J =6.4 Hz, 3H), 1.8 (m, 4H), 2.63 (m, 4H), 2.7 (m, 1H), 3.79 (m, 1H), 4.07(m, 1H), 4.54 (d, J = 2.0 Hz, 1H), 5.45 (d, J = 2 Hz, 1H), 6.42 (d, J =7.3 Hz, 1H), 6.59 (m, 1H), 6.64 (m, 4H), 6.8 (d, J = 8.7 Hz, 2H), 6.84(d, J = 8.7 Hz, 1H), 6.92 (t, J = 7.6 Hz, 1H), 7.09 d, J = 8.7 Hz, 2H) Fα-CH₃ β-CH₃ β-CH₃ H H 3 0.99 (d, 6H), 1.66 (m, 2H), 2.29 (m, 2H), 2.80(m, 4H), 4.01 (m, 2H), 4.60 (d, J = 2.3 Hz, 1H), 5.45 (d, J = 2.3 Hz,1H), 6.40 (d, 1H), 6.58-6.80 (m, 6H), 6.91 (t, 1H), 7.06 (d, 2H); MS m/z496.2 (M⁺) F H H β-CH₃ H H 3 1.19 (d, 3H), 1.71 (m, 4H), 2.65- 2.90 (m,5H), 3.80 (m, 1H), 4.08 (m, 1H), 4.60 (d, J = 2.2 Hz, 1H), 5.45 (d, J =2.2 Hz, 1H), 6.41 (d, 1H), 6.59-6.81 (m, 6H), 6.92 (t, 1H), 7.07 (d,2H); MS m/z 482.2 (M⁺) H β-CH₃ H β-CH₃ H H 4 0.99 (d, J = 6.6 Hz, 3H),1.15 (d, J = 6.4 Hz, 3H), 1.27 (m, 1H), 1.9- 2.9 (m's, 7H), 3.78 (m,1H), 4.05 (m, 1H), 4.52 (d, J = 1 Hz, 1H), 5.43 (d, J = 2.1 Hz, 1H),6.58 (m, 2H), 6.59 (d, J = 8.5 Hz, 2H), 6.6 (d, J = 3 Hz, 1H), 6.79 (d,J = 8.6 Hz, 2H), 6.82 (d, J = 7.4 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H) H β-CH₃ α-CH₃ β-CH₃ H H 4 0.98 (d, 6H), 1.13 (d, 3H), 1.62 (m, 2H), 2.33 (m,2H), 2.73 (m, 1H), 2.91 (m, 2H), 3.77 (m, 1H), 4.04 (m, 1H), 4.50 (d, J= 2.2 Hz, 1H), 5.42 (d, J = 2.1 Hz, 1H), 6.57- 7.03 (m, 1H); MS m/z492.3 (M⁺) H α-CH₃ β-CH₃ β-CH₃ H H 4 0.98 (d, 3H), 1.07 (d, 3H), 1.15(d, 3H), 1.62 (m, 2H), 2.35 (m, 2H), 2.71 (m, 1H), 2.89 (m, 2H), 3.71(m, 1H), 4.03 (m, 1H), 4.51 (d, J = 2.2 Hz, 1H), 5.42 (d, J = 2.0 Hz,1H), 6.56-6.82 (m, 9H), 7.02 (d, 2H); MS m/z 492.3 (M⁺) H β-CH₃ β-CH₃β-CH₃ H H 4 0.89 (2 d's, 6H), 1.14 (d, 3H), 2.19 (m, 2H7), 2.7 1-2.90(m, 3H), 3.05 (m, 2H), 3.74 (m, 1H), 4.03 (m, 1H), 4.51 (d, J = 2.2 Hz,1H), 5.42 (d, J = 2.2 Hz, 1H), 6.56-6.82 (m, 9H), 7.02 (d, 2H); MS m/z492.3 (M⁺) F β-CH₃ H β-CH₃ H H 3 0.99 (d, 3H), 1.15 (d, 3H), 1.26 (m,1H), 1.93 (m, 1H), 2.16 (m, 2H), 2.62-2.89 (m, 4H), 3.77 (m, 1H), 4.04(m, 1H), 4.60 (d, J = 2.3 Hz, 1H), 5.45 (d, J = 2.1 Hz, 1H), 6.40 (d,1H), 6.59-6.80 (m, 6H), 6.91 (t, 1H), 7.07 (d, 2H); MS m/z 496.2 (M⁺);[α]_(D) = +219° (c = 1.03, MeOH) H β-CH₃ α-CH₃ β-CH₃ H H 3 0.99 (d, 6H),1.18 (d, 3H), 1.6- 2.9 (m, 7H), 3.77 (m, 1H), 4.04 (m, 1H), 4.53 (d,1H), 5.45 (d, 1H), 6.4-7.07 (m, 11H) F β-CH₃ β-CH₃ β-CH₃ H H 3 0.89 (2d's, 6H), 1.13 (d, 3H), 2.18 (m, 2H), 2.72-2.91 (m, 3H), 3.01 (m, 2H),3.74 (m, 2H),. 4.05 (m, 2H), 4.60 (d, J = 2.3 Hz, 1H), 5.45 (d, J = 2.2Hz, 1H), 6.40 (d, 1H), 6.59-6.80 (m, 6H), 6.91 (t, 1H), 7.07 (d, 2H); MSm/z 510.0 (M⁺) H β-CH₃ H β-CH₃ H H 3 0.98 (d, 3H), 1.14 (d, 3H), 1.26(m, 1H), 1.92 (m, 1H), 2.16 (m, 2H), 2.62 (m, 1H), 2.70 (m, 2H), 2.88(m, 1H), 3.76 (m, 1H), 4.04 (m, 1H), 4.52 (d, J = 2.3 Hz, 1H), 5.43 (d,J = 2.2 Hz, 1H), 6.40 (d, 1H), 6.57-6.82 (m, 7H), 6.90 (t, 1H), 7.06 (d,2H); MS m/z 478.1 (M⁺) H α-CH₃ H β-CH₃ H H 4 1.0 (d, J = 6.2 Hz, 3H),1.17 (d, J = 6.4 Hz, 3H), 1.27-2.9 (m, 8H), 3.76 (m, 1H), 4.06 (m, 1H),4.53 (d, J = 2.1 Hz, 1H), 5.44 (d, J = 2 Hz, 1H), 6.59 (m, 4H), 6.6 (d,J = 3 Hz, 1H), 6.8 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 7.04(d, J = 8.7 Hz, 2H)

Example 11A Preparation of

To a mixture of the benzoxathiins obtained from Example 10A (0.0276 g,0.041 mmol) in acetonitrile (0.2 mL) was added iodotrimethylsilane(0.026 mL, 0.18 mmol) under nitrogen. The reaction was wrapped withaluminum foil and stirred at ambient temperature for 19.5 h. Thiourea(0.0141 g, 0.017 mmol) was added to the reaction and the resultingmixture was stirred for 1 h. The reaction was quenched with methanol andpartitioned between ethyl acetate and ice/saturated sodiumbicarbonate/5% sodium thiosulfate. The organic layer was collected,washed with brine, dried over sodium sulfate and concentrated in vacuo.The crude material was purified by silica gel chromatgoraphy to give thedesired product.

-   ¹H 500 MHz NMR(d6-acetone) ppm(δ): 0.99 (d, 3H), 1.17 (d, 3H), 1.27    (m, 1H), 1.97 (m, 1H), 2.18 (m, 2H), 2.63-2.90 (m, 4H), 3.79 (m,    1H), 4.07 (m, 1H), 4.60 (d, J=2.0 Hz, 1H), 5.46 (d, J=2.1 Hz, 1H),    6.60 (d, 2H), 6.71-6.83 (m, 8H), 7.05 (d, 2H).

Example 12 Preparation of 2(S)-Pyrrolidinyl-Propan-1-Ol

Potassium carbonate (41.4 g, 0.30 moles) was added to a solution of(S)-(+)-2-amino-1-propanol (11.27 g, 0.15 moles, Aldrich) in anhydrousacetonitrile (1.5 L) then 1,4-dibromobutane (17.9 mL, 0.15 moles,Aldrich) was added. The resulting mixture was refluxed for 24 hours thencooled to room temperature and filtered. The filtrate was concentratedunder vacuum to a straw-colored solid which was dissolved indichloromethane (150 mL) and again concentrated under vacuum to afford astraw-colored solid. This crude material, believed to be a mixture ofthe hydrobromide salt and the free base of the product, was againdissolved in dichloromethane (200 mL). Solid potassium carbonate and themixture was stirred vigorously for 3 hours then filtered andconcentrated under vacuum to afford a straw-colored solid. This solid,believed to still be partially the hydrobromide salt, was partitionedbetween dichloromethane (150 mL) and saturated aqueous potassiumcarbonate (50 mL). The layers (upper layer organic, lower layer aqueous)were separated and the aqueous layer was extracted with dichloromethane(2×100 mL). The combined organic layers were dried over magnesiumsulfate, filtered and evaporated to an amber oil. This crude product waspurified by short-path vacuum distillation to afford the title compoundas a colorless liquid (bp 53-54.5° C. at 1.5 mm Hg). NMR: (CDCl₃, 600MHz) δ 3.59 & 3.36 (2H, 2 dd, J=4, 10 Hz, H₁), 2.64-2.72 (1H, m, H₂),2.54-2.62 (4H, m, H_(2′) & H_(5′)), 1.72-1.80 (4H, m, H_(3′) &H_(4′)),1.04 (3H, d, J=7 Hz, H₃); MS (electrospray): m/e 130 (M+H), 112(M—OH). [α]_(D)+0.9°

Example 13 Preparation of 2(S)-(3-(R)-Methylpyrrolidinyl)-Propan-1-OlProdedure A

A solution of 2-(R)-methyl-1,4-dibromobutane (9.50 g, 0.041 moles) inanhydrous acetonitrile (25 mL) was added to a mixture of of(S)-(+)-2-amino-1-propanol (3.10 g, 0.041 moles, Aldrich) and potassiumcarbonate (11.42 g, 0.082 moles) in anhydrous acetonitrile (325 mL) .The resulting mixture was refluxed for 21 hours then cooled to roomtemperature and concentrated under vacuum to an oily solid residue.Ether (200 mL) and saturated aqueous potassium carbonate (25 mL) wereadded followed by just enough water to dissolve all solid. The layers(upper layer organic, lower layer aqueous) were separated and theaqueous layer was saturated with sodium chloride and extracted withdichloromethane (2×100 mL). The combined organic layers were dried overmagnesium sulfate and potassium carbonate, filtered and evaporated to ayellow liquid. This crude product was purified by short-path vacuumdistillation to afford the title compound as a colorless liquid (4.0 g,bp 54-57° C. at ˜3 mm Hg). A portion (2.31 g) of this material wasfurther purified by column chromatography on silica gel eluted with10:7:2:1 ethyl acetate: hexane : methanol: triethylamine to afford thetitle compound as a colorless liquid. NMR: (CDCl₃, 600 MHz) δ3.57 & 3.33(2H, 2 dd, J=5, 10 Hz, H₁), 3.06 (1 H, br s, OH), 2.85 (1H, dd, J=8, 9Hz, H_(2′a)), 2.68-2.73 (1H, m, H₂), 2.66-2.70 & 2.58-2.62 (4H, 2 m,H_(5′)), 2.18-2.26 (1 H, m, H_(3′)), 2.15 (1H, dd, J=7, 9 Hz, H_(2′b)),1.94-2.02 & 1.30-1.38 (4H, 2 m, & H_(4′)), 1.02 (3H, d, J=7 Hz,H_(3′Me)), 1.01 (3H, d, J=7 Hz, H₃); MS (electrospray): m/e 144 (M+H),126 (M—OH). [α]_(D)−0.5°

Prodedure B

Step 1:

(3R)-1-[(1S)-2-hydroxy-1-methylethyl]-3-methylpyrrolidine-2,5-dione.

(S)-(+)-2-Amino-1-propanol (7.80 mL, 100 mmol) was added to a hot (˜100°C.) solution of 2-(R)-methylsuccinic acid (13.2 g, 100 mmol) in toluene(1.0 L) (note: the acid is not soluble at room temperature but dissolvedon heating). The resulting cloudy mixture was refluxed under aDean-Stark trap for 24 hours (2 L heating mantle; variac setting 45).The resulting mixture was allowed to cool to room temperature thenconcentrated under vacuum to an oil. The crude imide was purified byflash chromatography on silica gel (65×280 mm column) eluted with 2:1hexane: acetone (note: the crude product was not very soluble in thissolvent; the crude product was thus dissolved in acetone (125 mL) andadsorbed onto silica gel (50 g) which was placed at the head of thepacked column) collecting 50 mL fractions after a 1.5 L forerun toafford the pure imide (in fractions 9-30) as a colorless liquid. ¹H NMR:(CDCl₃, 600 MHz) δ 4.28-4.38 (1H, m, H_(1′)), 3.91 (1H, dd, J=7, 12 Hz,H_(2′a)), 3.76 (1H, dd, J=3, 12 Hz, H_(2′b)), 2.91 (1H, dd, J=17, 9 Hz,H_(4α)), 2.80-2.88 (1H, m, H₃), 2.31 (1H, dd, J=17, 4 Hz, H_(4β)), 1.34& 1.33 (6H, 2 d, I=7 Hz, 2 CH₃s).

Step 2:

Chiral Prep HPLC.

Chiral preparative HPLC of the imide was performed on a Chiralpak AD100×250 mm column packed at 60 bar and eluted with 30% IPA/iso-octane at300 mL/min, with monitoring at 220 nm, using 1 g injections of sampledissolved in 50:50 hept/IPA. The retention time of the minordiastereomer was approx. 8.4 mins. and the major, positively rotatingdiastereomer was approximately 10.8 mins.

Step 3:

(2S)-2-[(3R)-3-methylpyrrolidin-1-yl]propan-1-ol.

Lithium aluminum hydride (96 mL of 1.0 M solution in ether, 0.096 moles)was added to a cold (ice bath) solution of(3R)-1-[(1S)-2-hydroxy-1-methylethyl]-3-methylpyrrolidine-2,5-dione(8.26 g, 0.048 moles) in anhydrous ether (565 mL). The cold bath wasremoved and the resulting mixture was stirred at room temperature for 17hours. The resulting mixture was cooled in an ice bath as water (3.7 mL)was added slowly dropwise (CALIMON: vigorous reaction, gas evolution)followed by 15% NaOH (3.7 mL) and additional water (11.0 mL). Theresulting mixture was stirred vigorously for 15 minutes then sonicatedfor 15 minutes and filtered. The collected solid was washed with ether(2×125 mL; stirred vigorously for 15 minutes then sonicated 15 minutesand filtered) and the combined filtrates were dried (MgSO4), filtered,and evaporated to a light yellow oil (5.76 g). The crude product waspurified by flash chromatography on silica gel (65×222 mm column) elutedwith 10:7:2:1 ethyl acetate: hexane : methanol: triethylamine collecting50 mL fractions after a forerun of 750 mL to afford the pure product (infractions 6-50) as a light yellow liquid. ¹H NMR: (CDCl₃, 600 M) δ 3.54& 3.32 (2H, 2 dd, J=5, 10 Hz, H₁), 3.30 (1H, br s, OH), 2.83 & 2.11 (2H,2 dd, J=8, 8 Hz, H_(2′)), 2.62-2.67 & 2.54-2.59 (2H, 2 m, H_(5′)),2.65-2.68 (2H, m, H₂), 2.15-2.24 (1H, m, H_(3′)), 1.92-1.98 & 1.28-1.34(2H, 2 m, H_(4′)), 1.00 (6H, d, J=7 Hz, 2 CH₃s); ¹³C NMR: (CDCl₃, 150MHz) δ 64.54, 58.02, 57.46, 48.87, 32.45, 31.67, 20.24, 12.49; MS(electrospray): m/e 144 (M+H). [α]_(D)−0.5° (c=1.0 in MeOH).

Example 14 Preparation of 2(S)-(3-(S)-Methylpyrrolidinyl)-Propan-1-Ol

A solution of 2-(S)-methyl-1,4-dibromobutane (2.70 g, 0.012 moles) inanhydrous acetonitrile (8 mL) was added to a mixture of of(S)-(+)-2-amino-1-propanol (0.882 g, 0.012 moles, Aldrich) and potassiumcarbonate (3.25 g, 0.024 moles) in anhydrous acetonitrile (92 mL) . Theresulting mixture was refluxed for 22 hours then cooled to roomtemperature and concentrated under vacuum to an oily white solid.Dichloromethane (50 mL) and saturated aqueous potassium carbonate (10mL) were added followed by just enough water to dissolve all solid. Thelayers (upper layer organic, lower layer aqueous) were separated and theaqueous layer was saturated with sodium chloride and extracted withdichloromethane (2×50 mL). The combined organic layers were dried overmagnesium sulfate and potassium carbonate, filtered and evaporated to alight yellow liquid. This crude product was purified by columnchromatography on silica gel eluted with 10:7:2:1 ethyl acetate :hexane: methanol : triethylamine to afford the title compound as a lightyellow liquid. NMR: (CDCl₃, 600 MHz) δ 3.52 & 3.32 (2H, 2 dd, J=5, 10Hz, H₁), 3.36 (1 H, br s, OH), 2.79 (1H, t, J=8 Hz, H_(2′a)), 2.54-2.58(1H, m, H₂), 2.66-2.72 & 2.56-2.62 (4H, 2 m, H_(5′)), 2.13-2.21 (1 H, m,H_(3′)), 2.08 (1H, td, J=8 Hz, H_(2′b)), 1.92-2.00 & 1.25-1.33 (4H, 2 m,& H_(4′)), 1.00 (3H, d, J=7 Hz, H_(3′Me)), 0.99 (3H, d, J=7 Hz, H₃); MS(electrospray): m/e 144 (M+H), 126 (M—OH). [α]_(D)+3.4°.

Example 15 Preparation of(2S)-2-[(3R,4R)-3,4dimethylpyrrolidin-1-yl]propan-1-Ol,(2S)-2-[(3S,4S)-3,4dimethylpyrrolidin-1-yl]propan-1-Ol, and(2S)-2-[(3S,4R)-3,4dimethylpyrrolidin-1-yl]propan-1-Ol

Step 1:

A mixture of 2,3-dimethyl succinic acid (21.2 g, 145.1 mmol) and acetylchloride (80 mL) was heated to reflux for 2.5h. The resulting solutionwas cooled to ambient temperature and concentrated. The residue wasdissolved in toluene and concentrated thrice. The residue was dissolvedin toluene, filtered, and concentrated to give an off-white solid. ¹HNMR showed a 1:1.5 cis:trans mixture of products, and the crude mixturewas used without further purification

Step 2:

The crude anhydrides (6.0 g, 46.8 mmol), obtained in Step 1, weredissolved in anhydrous dichloromethane (200 mL) and placed under aballoon of nitrogen. Triethylamine (7.2 mL, 51.7 mmol) and(S)-2-aminopropanol (4 mL, 51.4 mole) were added. The reaction initiallyturned cloudy and then went clear with a clear colorless residueclinging to the sides of the flask. The mixture was stired at ambienttemperature for 26.75 hours after which time the reaction wasconcentrated to an oil. The oil was dissolved in dichloroethane (200mL), acetic anhydride (22 mL, 233 mmol) added, and the solution washeated to reflux for 18.2 hours. The solution was cooled to ambienttemperature and stirred with saturated aqueous sodium bicarbonate. After1 hour, the mixture was partitioned between dichloromethane andsaturated aqueous sodium bicarbonate. The aqueous layer separated andextracted further with dichloromethane. The combined organic layers werewashed with brine, dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography on silica gel eluted withhexane-ethyl acetate (2:1) afforded a mixture of racemic trans-imides,as a colorless liquid, and a mixture of enriched cis-imide. Chiralseparation of the racemic trans imides on a ChiralCel® OD™ column(4.6×250 mm), available rom Daicel Industries, Ltd., eluted with 5%EtOH-heptane (20 injections) afforded the imide isomer A (S,R,R orS,S,S); [α]_(D)=+86° (c=1.0, MeOH), and imide isomer B (S,S,S or S,R,R);[α]_(D)=−35.3° (c=1.0, MeOH). The above cis-enriched mixture was furtherpurified by flash chromatography on silica gel eluted with hexane-ethylacetate (4:1) to afford the imide isomer C (S,S,R); [α]_(D)=+27° (c=1.0,MeOH), and the racemic trans imides.

Step 3:

Reduction of Isomer A.

To a stirred solution of 1.59 g (7.0 mmol) of imide isomer A, from Step2 above, in 80 mL of anhydrous diethyl ether was added lithium aluminumhydride (0.8 g, 21.1 mmol). The resulting mixture was placed under aballoon of nitrogen and stirred further for 17.6 hours at ambienttemperature. To this mixture was sequentially added, water (0.8 mL), 15%aqueous NaOH solution (0.8 mL), and water (2.4 mL), and then diethylether. The resulting mixture was sonicated and the aluminum salts wereremoved by filtration. The filtrate was dried (MgSO4), filtered, andevaporated to give a clear oil. Purification by flash chromatography onsilica gel eluted with ethyl acetate-hexane-methanol-triethylamine(13:5:1:1) afforded the (+)-(S,R,R or S,S,S)-pyrrolidine. ¹H 500 MHz NMR(CDCl₃, δ, ppm) 3.56 (dd, J=10.0, 4.0 Hz, 1H), 3.30 (dd, J=10.0, 7.0 Hz,1H), 2.87 (dd, J=9.5, 7.5 Hz, 2H), 2.70-2.77 (m, 1H), 2.31 (dd, J=9.0,7.0 Hz, 2H), 1.64-1.74 (m, 2H), 1.03 (d, J=6.5 Hz, 6H), 1.00( d, J=6.5Hz, 3H); MS (electrospray): m/z 158.4 (M+H); [α]_(D)=+44.1° (c=1.0,MeOH).

Step 4:

Reduction of Isomer B.

To a stirred solution of 1.41 g (6.2 mmol) of imide isomer B, from Step2 above, in 71 mL of anhydrous diethyl ether was added lithium aluminumhydride (0.71 g, 18.7 mmol). The resulting mixture was placed under aballoon of nitrogen and stirred further for 18 hours at ambienttemperature. To this mixture was sequentially added, water (0.71mL), 15%aqueous NaOH solution (0.71 mL), and water (2.1 mL), and then diethylether. The resulting mixture was sonicated and the aluminum salts wereremoved by filtration. The filtrate was dried (MgSO₄), filtered, andevaporated to an oily solid. Purification by flash chromatography onsilica gel eluted with ethyl acetate-hexane-methanol-triethylamine(13:5:1:1) afforded the (−)-(S,R,R or S,S,S)-pyrrolidine, as a lightyellow solid. ¹H 500 MHz NMR (CDCl₃, δ, ppm) 3.54 (dd, J 8.5, 3.5 Hz,1H), 3.30 (dd, J=8.5, 5.0 Hz, 1H), 2.82 (dd, J=7.5, 6.0 Hz, 2H),2.62-2.68 (m, 1H), 2.31 (dd, J=7.5, 6.0 Hz, 2H), 1.62-1.70 (m, 2H),0.99-1.03 (m, 9H,); MS (electrospray): m/z 158.3 (M+H); [α]_(D)=−40.5°(c=1.0, MeOH).

Step 5:

Reduction of Isomer C.

To a stirred solution of 0.7 g (3.1 mmol) of imide isomer C, from Step 2above, in 100 mL of anhydrous diethyl ether was added lithium aluminumhydride (0.35 g, 9.2 mmol). The resulting mixture was placed under aballoon of nitrogen and stirred further for 18.2 hours at ambienttemperature. To this mixture was sequentially added, water (0.35 mL),15% aqueous NaOH solution (0.35 mL), and water (1.1 mL), and thendiethyl ether. The resulting mixture was sonicated and the aluminumsalts were removed by filtration. The filtrate was dried (MgSO₄),filtered, and evaporated to a clear oil. Purification by flashchromatography on silica gel eluted with ethylacetate-hexane-methanol-triethylamine (13:5:1:1) afforded the(+)-(S,S,R)-pyrrolidine, as a clear oil. ¹H 500 MHz NMR (CDCl₃, δ, ppm)3.57 (dd, J=10.5, 4.5 Hz, 1H), 3.31 (dd, J=10.5, 7.0 Hz, 1H), 3.00 (dd,J=8.5, 6.5 Hz, 1H), 2.92 (dd, J=8.5, 6.5 Hz, 1H), 2.69-2.73 (m, 1H),2.18-2.27 (m, 4H), 1.02 (d, J=6.5 Hz, 3H), 0.94 (d, J=6.5 Hz, 3H), 0.93(d, J=6.5 Hz, 3H); MS (electrospray): m/z 158.3 (M+H); [α]_(D)=+1.9°(c=1.0, MeOH).

Pharmaceutical Composition

As a specific embodiment of this invention, 25 mg of the compound 11a,from Example 11, is formulated with sufficient finely divided lactose toprovide a total amount of 580 to 590 mg to fill a size 0, hard-gelatincapsule.

1. A compound of the formula:

wherein R¹ is selected from hydrogen or halo; R² is selected fromhydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃; R³ is selected from hydrogen,C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃; R⁴ is selected from C₁₋₃ alkyl, CH₂F,CHF₂, CF₃, or hydrogen with the proviso that R⁴ and R⁷ are notsimultaneously hydrogen; R⁵ is selected from hydrogen or hydroxyl; R⁶ isselected from hydrogen or hydroxyl; R⁷ is selected from C₁₋₃ alkyl, CH₂For hydrogen with the proviso that R⁴ and R⁷ are not simultaneouslyhydrogen; R⁸ is selected from hydrogen, C₁₋₃ alkyl or CH₂F; or apharmaceutically acceptable salt, stereoisomer, or chiral form thereof.2. The compound of claim 1 wherein R⁴ is CH₃; or a pharmaceuticallyacceptable salt, stereoisomer, or chiral form thereof.
 3. The compoundof claim 2 of the formula:

wherein R¹ is selected from hydrogen or halo; R² is selected fromhydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃; R³ is selected from hydrogen,C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃; R⁵ is selected from hydrogen or hydroxyl;R⁶ is selected from hydrogen or hydroxyl; R⁷ is selected from hydrogen,C₁₋₃ alkyl or CH₂F; R⁸ is selected from hydrogen, C₁₋₃ alkyl or CH₂F; ora pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 4. The compound of claim 3 wherein R¹ is selected from thegroup consisting of hydrogen and fluoro; or a pharmaceuticallyacceptable salt, stereoisomer, or chiral form thereof.
 5. The compoundof claim 4 selected from:

or a pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 6. The compound of claim 5 which is

or a pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 7. The compound of claim 5 which is

or a pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 8. The compound of claim 5 which is

or a pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 9. The compound of claim 5 which is

or a pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 10. The compound of claim 5 which is

or a pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 11. The compound of claim 2 of the formula:

wherein R¹ is selected from hydrogen or halo; R² is selected from thehydrogen, C₁₋₃ alkyl, CH₂F, CHF₂ or CF₃; R³ is selected from hydrogen,C₁₋₃ alky, CH₂F, CHF₂ or CF₃; R⁵ is selected from hydrogen or hydroxyl;R⁶ is selected from hydrogen or hydroxyl; R⁷ is selected from hydrogen,C₁₋₃ alkyl or CH₂F; R⁸ is selected from hydrogen, C₁₋₃ alkyl or CH₂F; ora pharmaceutically acceptable salt, stereoisomer, or chiral formthereof.
 12. The compound of claim 11 wherein R¹ is selected fromhydrogen or fluoro; or a pharmaceutically acceptable salt, stereoisomer,or chiral form thereof.
 13. The compound of claim 12 selected from:

(2S,3R)-5-fluoro-3-(4hydroxyphenyl)-2-[4-({(2R)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;

(2S,3R)-5-fluoro-3-(3-hydroxyphenyl)-2-[⁴-({(2R)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;

(2S,3R)-3-(4-hydroxyphenyl)-2-[4-({(2R)-2-[(3S)-3-methylpyrrolidin-1-yl]propyl}oxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol;


14. A pharmaceutical composition comprising a compound according toclaim 1 and a pharmaceuticaly acceptable carrier.
 15. A pharmaceuticalcomposition made by combining a compound according to claim 1 and apharmaceutically acceptable carrier.
 16. A process for making apharmaceutical composition comprising combining a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 17. A method ofeliciting an estrogen receptor modulating effect in a mammal in needthereof, comprising administering to the mammal a therapeuticallyeffective amount of a compound according to claim
 1. 18. The methodaccording to claim 17 wherein the estrogen receptor modulation effect isan estrogen receptor agonizing effect.
 19. The method according to claim17 wherein the estrogen receptor agonizing effect is an ERα receptoragonizing effect.
 21. The method according to claim 17 wherein theestrogen receptor modulation effect is an estrogen receptor antagonizingeffect.
 22. The method according to claim 17 wherein the estrogenreceptor antagonizing effect is an ERα receptor antagonizing effect. 23.A method of treating or preventing a disease in a mammal in need thereofby administering to the mammal a therapeutically effective amount of acompound according to claim 1, wherein said disease is selected from:bone loss, bone fractures, osteoporosis, glucocorticoid inducedosteoporosis, Paget's disease, abnormally increased bone turnover,periodontal disease, tooth loss, rheumatoid arthritis, osteoarthritis,periprosthetic osteolysis, osteogenesis imperfecta, metastatic bonedisease, hypercalcemia of malignancy, multiple myeloma, cartilagedegeneration, endometriosis, uterine fibroid disease, breast cancer,uterine cancer, prostate cancer, hot flashes, cardiovascular disease,impairment of cognitive function, cerebral degenerative disorders,restenosis, gynecornastia, vascular smooth muscle cell proliferation,obesity or incontinence.
 24. The method of claim 23 wherein the diseaseis osteoporosis.
 25. The method of claim 23 wherein the disease ismetastatic bone disease.
 26. A method of treating or preventing anestrogen dependent cancer in a mammal in need thereof by administeringto the mammal a therapeutically effective amount of a compound accordingto claim
 1. 27. A pharmaceutical composition comprising a compound ofclaim 1 and another agent selected from: an organic bisphosphonate; acathepsin K inhibitor; an estrogen; an estrogen receptor modulator; anandrogen receptor modulator; an inhibitor of osteoclast proton ATPase;an inhibitor of HMG-CoA reductase; an integrin receptor antagonist; anosteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin Danalogue; or a selective serotonin reuptake inhibitor; an aromataseinhibitor; or a pharmaceutically acceptable salt or mixture thereof. 28.A method of treating osteoporosis comprising administering to a mammalin need thereof a compound of claim 1 and another agent selected from:an organic bisphosphonate; a cathepsin K inhibitor; an estrogen; anestrogen receptor modulator; an androgen receptor modulator; aninhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoAreductase; an integrin receptor antagonist; an osteoblast anabolicagent; calcitonin; Vitamin D; a synthetic Vitamin-D analogue; aselective serotonin reuptake inhibitor; an aromatase inhibitor; or apharmaceutically acceptable salt or mixture thereof.
 29. A method oftreating bone loss comprising administering to a mammal in need thereofa compound of claim 1 and another agent selected from: an organicbisphosphonate; a cathepsin K inhibitor; an estrogen; an estrogenreceptor modulator; an androgen receptor modulator; an inhibitor ofosteoclast proton ATPase; an inhibitor of HG-CoA reductase; an integrinreceptor antagonist; an osteoblast anabolic agent; calcitonin; VitaminD; a synthetic Vitamin D analogue; a selective serotonin reuptakeinhibitor; an aromatase inhibitor; or a pharmaceutically acceptable saltor mixture thereof.
 30. A method of treating metastatic bone diseasecomprising administering to a mammal in need thereof a compound of claim1 and another agent selected from: an organic bisphosphonate; acathepsin K inhibitor; an estrogen; an estrogen receptor modulator; anandrogen receptor modulator; an inhibitor of osteoclast proton ATPase;an inhibitor of HMG-CoA reductase; an integrin receptor antagonist; anosteoblast anabolic agent; calcitonin; Vitamin D; a synthetic Vitamin Danalogue; a selective serotonin reuptake inhibitor; an aromataseinhibitor; or a pharmaceutically acceptable salt or mixture thereof. 31.A method of lowering cholesterol comprising administering to a mammal inneed thereof a compound of claim 1 and another agent selected from: anorganic bisphosphonate; a cathepsin K inhibitor; an estrogen; anestrogen receptor modulator; an androgen receptor modulator; aninhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoAreductase; an integrin receptor antagonist; an osteoblast anabolicagent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; or aselective serotonin reuptake inhibitor; or a cholesterol ester transferprotein inhibitor; a pharmaceutically acceptable salt or mixturethereof.
 32. A method of treating a tamoxifene-resistant breast cancerin a mammal in need thereof by administering to the mammal atherapeutically effective amount of a compound according to claim
 1. 33.The method of claim 23 wherein the disease is metastatic breast cancer.